AU2023206094B2 - Solid forms of a thienopyrimidinedione ACC inhibitor and methods for production thereof - Google Patents

Abstract

#$%^&*AU2023206094B220250904.pdf##### 1004799942 ABSTRACT The present invention provides solid forms of compounds useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, methods of producing the same, and methods of using the same in the treatment of ACC-mediated diseases. 1004799942 ABSTRACT Jul 2023 The present invention provides solid forms of compounds useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, methods of producing the same, and methods of using the same in the treatment of ACC-mediated diseases. 2023206094 18

Description

1004799942

SOLID FORMS SOLID OF A FORMS OF A THIENOPYRIMIDINEDIONE ACC THIENOPYRIMIDINEDIONE ACC INHIBITOR INHIBITOR AND AND 2023206094 18 Jul 2023

METHODS FOR METHODS FOR PRODUCTION PRODUCTION THEREOF THEREOF CROSS REFERENCE CROSS REFERENCETO TORELATED RELATED APPLICATIONS APPLICATIONS

[0001] This This

[0001] application application is a divisional is a divisional application application of Australian of Australian application application no. 2021209149, no. 2021209149,

which isis a adivisional which divisionalapplication applicationof of Australian Australian application application no.no. 2017226267, 2017226267, the entire the entire

disclosures ofofwhich disclosures whichareare incorporated incorporated herein herein by reference. by reference. This application This application claims claims the the benefit benefit under3535U.S.C. under U.S.C.§ 119(e) § 119(e) to U.S. to U.S. Provisional Provisional Application Application NumberNumber 62/302,755, 62/302,755, filed 2, filed on March on March 2, 2016, and 2016, andU.S. U.S.Provisional Provisional Application Application No. 62/303,237, No. 62/303,237, filed onfiled Marchon3,March 3, 2016, 2016, both both of which of which are incorporated are incorporatedherein hereinbybyreference. reference.

BACKGROUNDOF BACKGROUND OFTHE THE INVENTION INVENTION

[0002] Obesity

[0002] Obesity is a health crisiscrisis is a health of epic of epic proportions. proportions. The health The health burden burden of obesity, measured measured of obesity, by quality-adjusted by quality-adjustedlife-years life-yearslost lostper peradult, adult, has hassurpassed surpassedthat thatofofsmoking smoking to become to become the the most most serious, preventable serious, causeofof preventable cause death.In In death. thethe U.S.,about U.S., about 34% 34% of adults of adults have have obesity, obesity, up31% up from from 31% in 1999 in 1999and andabout about15%15% in the in the years years 19601960 through through 1980. Obesity 1980. Obesity increasesincreases the rate the rate of mortality of mortality

fromall from all causes causesfor forboth bothmen menandand women women at allatages all ages and and in allinracial all racial and ethnic and ethnic groups. groups. ObesityObesity

also leads also leads to to social social stigmatization stigmatization and anddiscrimination, discrimination,which which decreases decreases quality quality of of life life dramatically. The dramatically. Thechronic chronic diseases diseases that that result result from from obesity obesity costcost the the U.S.U.S. economy economy more more than than $150 billion $150 billion inin weight-related weight-relatedmedical medical bills bills each each year. year. Furthermore, Furthermore, about about half half of theof the obese obese population,and population, and25% 25% of the of the general general population, population, have have metabolic metabolic syndrome, syndrome, a condition a condition associated associated

with abdominal with abdominal obesity, obesity, hypertension, hypertension, increased increased plasma plasma triglycerides, triglycerides, decreased decreased HDL HDL cholesterol, and cholesterol, and insulin insulin resistance, resistance, which whichincreases increases thethe risk risk fortype-2 for type-2 diabetes diabetes (T2DM), (T2DM), strokestroke

and coronary and coronaryheart heartdisease disease (Harwood, (Harwood, Expert Expert Opin. Opin. Ther. Targets Ther. Targets 9: 267, 9: 267, 2005). 2005).

[0003] DietDiet

[0003] and and exercise,even exercise, even when when used used in in conjunctionwith conjunction withthe thecurrent current pharmacotherapy, pharmacotherapy, do not do not provide providesustainable sustainableweight weight loss loss needed needed for long-term for long-term health health benefit. benefit. Currently, Currently, only a only a few anti-obesity few anti-obesitydrugs drugsareareapproved in the approved U.S., in the the the U.S., fat fat absorption inhibitor absorption orlistat inhibitor (Xenical), orlistat (Xenical©), the 5-HTc the 5-HT2c antagonist antagonist lorcaserin lorcaserin (Belviq©), (Belviq), and the the combination andcombination therapy therapy phentermine/topiramate phentermine/topiramate

(Qsymia*).Unfortunately, (Qsymia®). Unfortunately, poorpoor efficacy efficacy and unappealing and unappealing gastrointestinal gastrointestinal side effects side effects limit limit the the use of orlistat. use of orlistat. Surgery canbebeeffective Surgery can effectivebut butisislimited limitedtotopatients patientswith withextremely extremely high high BodyBody

MassIndices Mass Indices(BMI) (BMI) and and the low the low throughput throughput of surgery of surgery limits limits the impact the impact of this of this modality modality to to about 200k about 200kpatients patientsperperyear. year.TheThe majority majority of obesity of obesity drugsdrugs in clinical in clinical development development are are designedtotoreduce designed reducecaloric caloricintake intake through through central central action action in the in the CNS CNS (e.g., (e.g., anorectics anorectics and satiety and satiety

agents). However, agents). However,the the FDAFDA has taken has taken an unfavorable an unfavorable positionposition against CNS-active against CNS-active agents, dueagents, to due to their modest their efficacyand modest efficacy and observed/potential observed/potential side-effect side-effect profiles. profiles.

1

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[0004] The continuing

[0004] The continuing and increasing and increasing problem problem of obesity, obesity, ofand and the the current current lack of safe andof lack safe and it, highlight highlight the the overwhelming for for need new new drugsdrugs to treat this this 2023206094 18 Jul 2023

effective drugs effective drugs for for treating treating it, overwhelming need to treat

condition and condition andits its underlying underlyingcauses. causes.

[0005] Another

[0005] Another problem problem ongoingongoing is the lack theantifungal is of drugs withdrugs lack of antifungal activity activity withagainst against a broad a broad range ofoffungal range fungalpathogens. pathogens.Often, Often, a given a given antifungal antifungal drug drug will have will have activity activity against against one fungal one fungal

species but species but lack lackactivity activity against against other, other, even evenclosely closelyrelated, related,species, species,such suchas asCandida Candida albicans, albicans,

Candida Candida krusei,and krusei, and Candidaparapsilosis. Candida parapsilosis.

SUMMARY SUMMARY

[0006] The The

[0006] compound, compound, (R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4 (R)-2-(1-(2-(2-methoxyphenyl)-2-(tetrahydro-2H-pyran-4-

yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl) yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno|2,3-d]pyrimidin-3(4H)-yl)-

2-methylpropanoic 2-methylpropanoic acid, acid, designated designated herein herein as Compound as Compound 1, has 1, has the the formula: formula:

0 CN N ~NN XCOH CO 2 H

O S S N N -k0 O

O O

Compound1.1. Compound

[0007] The The

[0007] present present disclosure disclosure relatestotovarious relates various crystalline ofCompound formsof crystalline forms 1, processes Compound 1, processes for making for Compound making Compound 1 and 1its andvarious its various forms,forms, and methods and methods of using of using such such forms. forms.

[0008] Compound

[0008] Compound 1 also 1provides also provides formsforms further further described described herein herein as "Compound as "Compound 1 Form1 I," Form I," "Compound "Compound 1 Form 1 Form II,""Compound II," "Compound 1 Form 1 Form III,"III," "Compound "Compound 1 Form 1 Form IV," "Compound IV," "Compound 1 Form 1 Form V," "Compound V," "Compound 1 1Form Form VI,""Compound VI," "Compound 1 Form 1 Form VII,"VII," "Compound "Compound 1 Form1 VIII," Form VIII," and and "amorphous Compound "amorphous 1." Compound 1."

[0009] Additional

[0009] Additional crystallineforms crystalline Compound formsofofCompound 1 are 1 are further herein. describedherein. furtherdescribed

[0010] In some

[0010] In some embodiments, embodiments, crystalline crystalline forms of of forms Compound Compound may include 1 may1 include a salt, a salt, a co a co-

crystal, aa solvate, crystal, solvate, or or aa hydrate hydrate of of Compound Compound 1. 1.

[0011] In some

[0011] In some embodiments, embodiments, crystalline crystalline forms forms of of Compound Compound may include 1 may 1include a salt a salt of of Compound1. 1.InInsome Compound someembodiments, embodiments, Compound Compound 1 provide 1 provide forms forms further further described described herein herein asas

"Compound "Compound 1 Sodium 1 Sodium Form Form I," I," "Compound "Compound 1 Sodium 1 Sodium Form"Compound Form II," II," "Compound 1 Calcium 1 Calcium Form Form I," "Compound I," "Compound 1 1Magnesium Magnesium Form Form I," I," "Compound "Compound 1 Diethanolamine 1 Diethanolamine Form Form I," "Compound I," and and "Compound 1 Piperazine 1 Form Piperazine Form I." I."

[0012] SomeSome

[0012] embodiments embodiments provide for a for provide a process process of preparing of preparing Compound 1, or 1,a or Compound salt or or a salt co-co

crystal thereof, crystal thereof, comprising: comprising:

2

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(a) (a) contacting compound contacting G-2-a: compound G-2-a:

0 2023206094 18 Jul 2023

Br Br / N N S S N- OO IZ N H O H G-2-a G-2-a with oxazole with oxazoleunder under conditions conditions sufficient sufficient to to form form compound compound G-9-a: G-9-a: 0 O N N 1 N o N O S IZ O N H O H G-9-a G-9-a

(b) contacting (b) contactingcompound G-9-a with compound G-9-a with compound compound(R)-G-1-a: (R)-G-1-a: Br Br

O

(R)-G-1-a (R)-G-1-a

underconditions under conditionssufficient sufficienttotoform form a compound a compound G-4-a: G-4-a:

0 O NO N O N O S N O N o o o~

O 0 O

G-4-a G-4-a

and and

(c) hydrolyzing (c) hydrolyzing compound G-4-aunder compound G-4-a underconditions conditions sufficient sufficient totoform formCompound 1. Compound 1.

[0013] SomeSome

[0013] provideprovide embodiments embodiments for a process for a process of preparing of preparing Compound Compound 1, or salt or salt 1, or co- or co crystal thereof, crystal thereof, comprising: comprising:

(a) contacting (a) compound contacting compound (R)-G-5-a (R)-G-5-a or an or an oxygen oxygen anion thereof: anion thereof:

OH OH O O

3

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(R)-G-5-a (R)-G-5-a 2023206094 18 Jul 2023

with aa sulfonylating with sulfonylatingreagent reagentunder under conditions conditions sufficient sufficient to form to form compound compound (R)-G-6-a: (R)-G-6-a:

S

0 O 0 O

(R)-G-6-a (R)-G-6-a

(b) contacting (b) contacting compound (R)-G-6-awith compound (R)-G-6-a with a bromide a bromide saltsalt under under conditions conditions sufficienttotoform sufficient form compound(R)-G-1-a: compound (R)-G-1-a: Br Br

O O

(R)-G-1-a (R)-G-1-a

(c) contacting (c) contacting compound compoundG-2-a: G-2-a:

O O BrNN Br S S N--OO0 IZ N H H G-2-a G-2-a with oxazole with oxazoleunder under conditions conditions sufficient sufficient to to form form compound compound G-9-a: G-9-a: 0 o N N N o N O S O N H H G-9-a G-9-a (d) contacting (d) compound contacting compound G-9-a G-9-a with with compound compound (R)-G-1-a(R)-G-1-a under sufficient under conditions conditions tosufficient form a to form a G-4-a: compoundG-4-a: compound

0 NO N O N O S O N o 0 o NNo 0 0

O O

G-4-a G-4-a

and (e) and (e) hydrolyzing hydrolyzing compound G-4-aunder compound G-4-a underconditions conditions sufficient sufficient totoform formCompound 1. Compound 1.

4

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2023206094 18 Jul 2023

BRIEF BRIEF DESCRIPTION OF THE DESCRIPTION OF THE DRAWINGS DRAWINGS

[0014]

[0014] Figure depictsa aX-Ray 1Adepicts Figure 1A X-Ray powder powder diffraction (XRPD)(XRPD) diffraction Form I of of Form Iofof pattern pattern

Compound1.1. Compound

[0015]

[0015] Figure lBdepicts Figure 1B another depictsanother X-Ray X-Ray powder powder diffraction (XRPD) (XRPD) diffraction pattern pattern of ofForm I of Form Iof

Compound1.1. Compound

[0016]

[0016] Figure 22 depicts Figure theellipsoid depictsthe diagram ellipsoiddiagram of of Form Form of Compound I ofI Compound 1. 1.

[0017]

[0017] Figure depictsa adifferential 3Adepicts Figure 3A scanning differentialscanning calorimeter calorimeter (DSC) curve curve (DSC) ofIForm of Form of I of Compound1.1. Compound

[0018]

[0018] Figure 3Bdepicts Figure 3B another depictsanother differential scanning differentialscanning calorimeter (DSC)(DSC) calorimeter curve of Formof curve I Form of I of Compound1.1. Compound

[0019]

[0019] Figure 4A Figure depicts aa thermogravimetric 4A depicts (TGA) of analysis(TGA) thermogravimetric analysis ofForm ofCompound Form IIof 1. Compound 1.

[0020]

[0020] Figure 4Bdepicts Figure 4B another depictsanother thermogravimetric thermogravimetric analysis analysis of Form of (TGA) (TGA) Form I of I of

Compound1.1. Compound

[0021]

[0021] Figure 55 depicts Figure depictsthe X-Ray theX-Ray powder powder diffraction diffraction pattern pattern of Form of Form II of II of Compound Compound 1. 1.

[0022]

[0022] Figure 66 depicts Figure theX-Ray depictsthe X-Ray powder powder diffraction diffraction pattern pattern of Form III ofIII of Form of Compound Compound 1. 1.

[0023]

[0023] Figure 7Adepicts Figure 7A X-Ray depictsa aX-Ray powder powder diffraction diffraction pattern pattern ofIV of Form Form IV of Compound of Compound 1. 1.

[0024]

[0024] Figure 7Bdepicts Figure 7B another depictsanother X-Ray X-Ray powder powder diffraction diffraction pattern of FormofIVForm pattern of IV of Compound1.1. Compound

[0025]

[0025] Figure 88 depicts Figure thedifferential depictsthe differential scanning calorimeter scanningcalorimeter (DSC) (DSC) curvecurve of Form IV of IV of of Form Compound1.1. Compound

[0026]

[0026] Figure 99 depicts Figure thethermogravimetric depictsthe thermogravimetric analysis analysis (TGA) of FormofIV (TGA) Form IV of Compound of Compound 1. 1.

[0027]

[0027] Figure 10depicts Figure 10 theX-Ray depictsthe X-Ray powder powder diffraction diffraction pattern pattern of VForm of Form V of Compound of Compound 1. 1.

[0028]

[0028] Figure 11A Figure 11A depicts depicts a X-Ray a X-Ray powder powder diffraction diffraction pattern pattern ofVIForm of Form VI of Compound of Compound 1. 1.

[0029]

[0029] Figure depicts 11Bdepicts Figure 11B another another X-Ray X-Ray powder powder diffraction patternpattern diffraction VIForm of Formof of VI of Compound1.1. Compound

[0030]

[0030] Figure 12depicts Figure 12 thedifferential depictsthe scanning differentialscanning calorimeter calorimeter (DSC) curvecurve (DSC) of VI of Form of VI of Form Compound1.1. Compound

[0031]

[0031] Figure 13 depictsthe 13 depicts thermogravimetricanalysis thethermogravimetric analysis (TGA)ofofForm (TGA) VIof FormVI ofCompound 1. Compound 1.

[0032]

[0032] Figure depictsthe 14depicts Figure 14 X-Ray theX-Ray powder powder diffraction diffraction pattern pattern of VII of Form Formof VII of Compound Compound 1. 1.

[0033]

[0033] Figure depicts 15Adepicts Figure 15A a X-Ray a X-Ray powder powder diffraction diffraction pattern pattern ofVIII of Form Formof VIII of Compound Compound 1. 1.

[0034]

[0034] Figure depicts 15Bdepicts Figure 15B another another X-Ray X-Ray powder powder diffraction patternpattern diffraction of Formof VIII of VIII of Form Compound1.1. Compound

[0035]

[0035] Figure depictsthe 16depicts Figure 16 thedifferential differentialscanning calorimeter scanningcalorimeter (DSC) curvecurve (DSC) of Form FormofVIII of of VIII Compound1.1. Compound

5

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[0036]

[0036] Figure 17 depicts Figure 17 depictsthe thethermogravimetric thermogravimetricanalysis analysis(TGA) (TGA)ofofForm FormVIII VIIIofof Compound Compound 2023206094 18 Jul 2023

1. 1.

[0037]

[0037] Figure 18depicts Figure 18 X-Ray theX-Ray depictsthe powder powder diffraction diffraction pattern pattern of amorphous CompoundCompound of amorphous 1. 1.

[0038]

[0038] Figure Figure 19 depictsthe 19 depicts X-Ray powder theX-Ray diffractionpattern powder diffraction patternof of Compound1 1 Sodium Compound Sodium

FormI.I. Form

[0039]

[0039] Figure 20depicts Figure 20 depictsthe differential scanning thedifferential calorimeter scanningcalorimeter (DSC) curvecurve (DSC) of Compound of Compound 1 1 SodiumForm Sodium FormI.I.

[0040]

[0040] depictsthe 21 depicts Figure 21 thermogravimetricanalysis thethermogravimetric analysis (TGA)ofofCompound (TGA) Compound 1 Sodium 1 Sodium FormI.I. Form

[0041]

[0041] depictsthe Figure 22 depicts theX-Ray diffractionpattern powder diffraction X-Ray powder pattern Compound1 1 Sodium Compound of of Sodium

FormII. Form II.

[0042]

[0042] Figure 23depicts Figure 23 depictsthe differential scanning thedifferential calorimeter scanningcalorimeter (DSC) curvecurve (DSC) of Compound of Compound 1 1 SodiumForm Sodium FormII. II.

[0043]

[0043] depictsthe Figure 24 depicts thermogravimetricanalysis thethermogravimetric analysis (TGA)ofofCompound (TGA) 1 Sodium Compound 1 Sodium FormII. Form II.

[0044]

[0044] Figure 25depicts Figure 25 depictsthe X-Ray theX-Ray powder powder diffraction diffraction pattern pattern of Compound 1 Calcium1 Calcium of Compound FormI.I. Form

[0045]

[0045] Figure Figure 26 thedifferential depictsthe 26depicts differential scanning calorimeter scanningcalorimeter (DSC) curvecurve (DSC) of Compound of Compound 1 1 Calcium Form Calcium FormI.I.

[0046]

[0046] depictsthe Figure 27 depicts thermogravimetricanalysis thethermogravimetric analysis (TGA)ofofCompound (TGA) Compound 1 Calcium 1 Calcium FormI.I. Form

[0047]

[0047] depictsthe Figure 28 depicts X-Ray powder theX-Ray diffractionpattern powder diffraction patternof of Compound1 1Magnesium Compound Magnesium

FormI.I. Form

[0048]

[0048] Figure 29depicts Figure 29 thedifferential depictsthe differential scanning calorimeter scanningcalorimeter (DSC) (DSC) curvecurve of Compound of Compound 1 1 MagnesiumForm Magnesium Form I. I.

[0049]

[0049] Figure 30 Figure depictsthe 30 depicts thermogravimetricanalysis thethermogravimetric analysis (TGA)ofofCompound (TGA) 1 Magnesium Compound 1 Magnesium FormI.I. Form

[0050]

[0050] Figure 31depicts Figure 31 X-Ray theX-Ray depictsthe powder powder diffraction diffraction pattern pattern of Compound of Compound 1 1 Diethanolamine Form Diethanolamine FormI.I.

[0051]

[0051] Figure 32depicts Figure 32 thedifferential depictsthe scanningcalorimeter differential scanning calorimeter (DSC) (DSC) curvecurve of Compound of Compound 1 1 Diethanolamine Form Diethanolamine FormI.I. Figure

[0052] Figure

[0052] thethe 33 depicts 33 depicts thermogravimetricanalysis thermogravimetric (TGA) analysis(TGA) of of Compound Compound 1 1 Diethanolamine Form Diethanolamine FormI.I.

[0053]

[0053] Figure Figure 34 the X-Ray depicts the 34 depicts powderdiffraction X-Ray powder pattern of diffraction pattern Compound 1 1Piperazine of Compound Piperazine FormI.I. Form

6

1004799942

[0054] Figure

[0054] Figure 35 depicts 35 depicts thethe scanning calorimeter differential scanning differential (DSC)curve calorimeter (DSC) Compound curveofofCompound 1 1 2023206094 18 Jul 2023

PiperazineForm Piperazine FormI. I.

Figure

[0055] Figure

[0055] 36 depicts thethe 36 depicts thermogravimetric thermogravimetric analysis analysis (TGA) (TGA) of Compound of Compound 1 Piperazine 1 Piperazine

FormI.I. Form

[0056] FigureFigure

[0056] 37 depicts 37 depicts the differential the differential scanning scanning calorimeter calorimeter (DSC) (DSC) curve of Form II of curve of Form II of Compound1.1. Compound

[0057]

[0057] Figure 38depicts Figure 38 thedifferential depictsthe calorimeter scanningcalorimeter differential scanning (DSC) curvecurve (DSC) of III of Form Formof III of

Compound1.1. Compound

[0058] Figure

[0058] Figure the the 39 depicts 39 depicts differentialscanning differential (DSC) calorimeter(DSC) scanningcalorimeter curve of of curve Form Form V ofV of Compound1.1. Compound

[0059] Figure

[0059] Figure the the 40 depicts 40 depicts scanningcalorimeter differential scanning differential (DSC) calorimeter (DSC) curveofofForm curve FormVII of of VII Compound1.1. Compound

DETAILED DESCRIPTION DETAILED DESCRIPTIONOF OF CERTAIN CERTAINEMBODIMENTS EMBODIMENTS 1. General 1. Generaldescription description United

[0060] United

[0060] States States Published Published Patent Patent Application Number ApplicationNumber 2013/0123231 2013/0123231 Al, published A1, published

May16,16,2013, May 2013,andand incorporated incorporated herein herein by reference by reference in itsinentirety, its entirety, discloses discloses certain certain

thienopyrimidinedione thienopyrimidinedione compounds compounds thattobind that bind and to and inhibit inhibit Acetyl Acetyl CoA Carboxylases CoA Carboxylases 1 and 2. 1 and 2. Such compounds Such compoundsinclude includeCompound Compound1: 1:

N S S 0C02H N N10 XCOH N

0 O 0 O

Compound 1. Compound 1.

Compound

[0061] Compound

[0061] 1, ((R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4 1, (R)-2-(1-(2-(2-methoxyphenyl)-2-(tetrahydro-2H-pyran-4-

yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl) yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-

2-methylpropanoic 2-methylpropanoic acid), acid), is is designated designated as compound as compound number number 1-181, I-181, and and the synthesis the synthesis of of Compound Compound 1 is1described is described in detail in detail at Example at Example 76 of 76 ofPatent U.S. U.S. Patent Publication Publication 2013/0123231. 2013/0123231.

[0062] Compound

[0062] Compound 1 isinactive 1 is active in a variety a variety ofand of assays assays and therapeutic therapeutic models, including including models, those those demonstratinginhibition demonstrating inhibitionof of ACCl ACC1 and/or and/or ACC2, ACC2, inhibition inhibition of fattyof fattysynthesis, acid acid synthesis, and and stimulation ofoffatty stimulation fatty acid acid oxidation. oxidation. ItItwould wouldbe be desirable desirable to to provide provide solid solid forms forms of Compound of Compound 1 1 that impart that characteristics such impart characteristics suchasasimproved improved aqueous aqueous solubility, solubility, stability, stability, andand easeease of of formulation. formulation.

1004799942

[0063] AlsoAlso

[0063] disclosed disclosed areare novel novel syntheticmethods synthetic methodsforforproducing producingCompound Compound 1 and 1 and analogs analogs 2023206094 18 Jul 2023

thereof, as thereof, as well as novel well as novel intermediates intermediatesininthe thesynthesis synthesisof of such such compounds. compounds. Such methods Such methods and and intermediatesare intermediates areamenable amenable to large to large scale scale production, production, owing owing to yields, to high high yields, favorable favorable

physicochemical physicochemical properties, properties, andand reduced reduced usetoxic use of of toxic reagents reagents or solvents or solvents compared compared to the to the state state of the art. of the art.

2. Solidforms 2. Solid forms of ofCompound Compound 11

[0064] In some

[0064] In some embodiments, embodiments, the present the present invention invention provides provides a solidform a solid formofofCompound Compound1, 1, or aa salt, or salt,co-crystal, co-crystal,solvate, solvate,or orhydrate hydrate thereof thereof. In In some embodiments, some embodiments, the the solid solid formform of of Compound Compound 1 is 1aissalt a salt or or co-crystal.In Insome co-crystal. some embodiments, embodiments, theorsalt the salt or co-crystal co-crystal is a is a pharmaceuticallyacceptable pharmaceutically acceptable saltsalt or or co-crystal co-crystal thereof. thereof. In In some some embodiments, embodiments, the present the present

invention provides invention providesa asolid solidform form of of Compound Compound 1, or a1, pharmaceutically or a pharmaceutically acceptable acceptable salt thereof. salt thereof.

In some In embodiments, some embodiments, the present the present invention invention provides provides a solida form solidofform of Compound Compound 1, or a 1, or a pharmaceuticallyacceptable pharmaceutically acceptable co-crystal co-crystal thereof. thereof. In some In some embodiments, embodiments, the invention the present present invention providesa asolid provides solidform formofofCompound Compound 1, or 1, or a pharmaceutically a pharmaceutically acceptable acceptable salt thereof, salt thereof, that is that is substantially free substantially free of of impurities. impurities. AsAsused used herein,thethe herein, term term "substantially "substantially freefree of impurities" of impurities"

meansthat means thatthe thecompound compound contains contains no significant no significant amountamount of extraneous of extraneous matter. matter. Such Such extraneous extraneous

matter may matter mayinclude include residual residual solvents, solvents, or or anyany other other impurities impurities that that may may result result from from the the preparationof, preparation of, and/or and/orisolation isolationof, of, Compound Compound1. In1.certain In certain embodiments, embodiments, at leastatabout least 95% about by 95% by weightofofCompound weight Compound1 is 1present. is present. In still In still otherother embodiments embodiments of the invention, of the invention, at leastatabout least about 99%bybyweight 99% weight of Compound of Compound 1 is present. 1 is present. In certain In certain embodiments, embodiments, at least at least about 95%about 95% by weight by weight of Compound of 1, aassalt Compound 1, as a salt or or co-crystal co-crystal thereof, thereof, is is present.In still present. In still other other embodiments embodiments of theof the invention, at invention, at least least about 99%byby about 99% weight weight of Compound of Compound 1, as a 1,salt as aorsalt or co-crystal co-crystal thereof thereof is present. is present.

According

[0065] According

[0065] to one to one embodiment, embodiment, Compound Compound 1 is present 1 is present in aninamount of atofleast an amount at least about about

97.0, 97.5, 97.0, 97.5, 98.0, 98.0, 98.5, 99.0, 99.5, 98.5, 99.0, 99.5, or or 99.8 99.8 weight weightpercent percentwhere the the where percentages percentages are based are based on theon the total weight total weightofofthe composition. the composition.According Accordingtotoanother embodiment, another embodiment,Compound Compound 11 contains contains no no

morethat more thatabout about3.03.0area areapercent percent HPLC HPLC of total of total organic organic impurities impurities and, and, in in certain certain embodiments, embodiments,

no more no morethat thatabout about1.51.5area area percent percent HPLC HPLC total total organic organic impurities impurities relative relative to thetototal the total area area of of the the HPLCchromatogram. HPLC chromatogram. In other In other embodiments, embodiments, Compound Compound 1 contains 1 contains no more no more than than aboutabout 1.0% 1.0%

area percent area percent HPLC HPLC of any of any single single impurity, impurity, and, and, in certain in certain embodiments, embodiments, no more no more than than about 0.5 about 0.5 area percent area percent HPLC HPLC of any of any single single impurity, impurity, relative relative to the to the total total areaarea of the of the HPLCHPLC chromatogram. chromatogram.

[0066] In some

[0066] In some embodiments, embodiments, Compound Compound 1 is present 1 is present in aninenantiomeric an enantiomeric excess excess (e.e.)ofof (e.e.)

about 90.0 about 90.0toto99.95 99.95percent. percent.InInsome some embodiments, embodiments, Compound Compound 1 isinpresent 1 is present in an enantiomeric an enantiomeric

excess (e.e.) excess (e.e.) of of at at least least about about 90.0, 90.0, 91.0, 91.0, 92.0, 92.0, 93.0, 94.0, 95.0, 93.0, 94.0, 95.0, 96.0, 97.0, 97.5, 96.0, 97.0, 97.5, 98.0, 98.0, 98.5, 98.5, 99.0, 99.0,

1004799942

99.5, 99.7, 99.5, 99.7, 99.8, 99.8, 99.9, 99.9, or 99.95 percent. or 99.95 percent.InInsome some embodiments, embodiments, Compound Compound 1 is optically 1 is optically pure, pure, 2023206094 18 Jul 2023

and substantially and substantially free free of ofits its (S)-enantiomer. (S)-enantiomer.

[0067] In some

[0067] In some embodiments, embodiments, Compound Compound 1 is present 1 is present as a as a free free acid. acid. In In some some embodiments, embodiments,

Compound Compound 1 is 1present is present as aassalt. a salt.In some In some embodiments, embodiments, CompoundCompound 1 is 1 is present as present a as a pharmaceuticallyacceptable pharmaceutically acceptable salt. salt. In some In some embodiments, embodiments, Compound Compound 1 is 1 is present as present as a co-crystal. a co-crystal.

In some

[0068] In some

[0068] embodiments, embodiments, Compound 1 is an 1amorphous Compound form ofform is an amorphous a salt salta or of aor a co-crystal co-crystal of of Compound1.1. Compound

[0069] In some

[0069] In some embodiments, embodiments, Compound Compound 1 1 is a form is a crystalline crystalline form of a salt or of a salt or aofco-crystal a co-crystal of Compound Compound 1. some 1. In In some embodiments, embodiments, the crystalline the crystalline form of form a saltofor a salt or co-crystal co-crystal of Compound of Compound I I is: Compound is: Compound 11 Sodium SodiumForm Form I,I,Compound Compound 1 Sodium 1 Sodium FormForm II, Compound II, Compound 1 Calcium 1 Calcium Form I, Form I,

Compound Compound 1 Magnesium 1 Magnesium FormForm I, Compound I, Compound 1 Diethanolamine 1 Diethanolamine Form Form I, I, or Compound or Compound 1 1 PiperazineForm Piperazine FormI. I.

[0070] The The

[0070] structure structure depicted depicted for Compound forCompound is alsomeant 1 is1 also to to meant includeall include tautomeric forms all tautomeric forms

of Compound of 1. Additionally Compound 1. Additionally structures structures depicted depicted here here are aremeant also also to meant to include include compounds compounds that that differ only differ in the only in the presence ofone presence of oneorormore more isotopically isotopically enriched enriched atoms. atoms. For example, For example, compounds compounds

havingthe having thepresent presentstructure structureexcept except forfor thereplacement the replacement of hydrogen of hydrogen by deuterium by deuterium or tritium, or tritium, or or the replacement the replacement ofof a a carbon carbon by by a 31 C- a ¹³C- or 4 C-enriched or ¹C-enriched carboncarbon are within are within the ofscope the scope this of this invention. invention.

It has

[0071] It has

[0071] been been found found that Compound thatCompound 1 can 1 can exist in in exist a avariety of solid variety of solid forms. Such forms forms. Such forms

include polymorphs, include polymorphs, solvates, solvates, hydrates, hydrates, and and amorphous. amorphous. Allforms All such suchare forms are contemplated contemplated by the by the present invention. present invention. InIncertain certainembodiments, embodiments, the present the present invention invention provides provides Compound Compound 1 as a 1 as a mixtureofofone mixture oneorormore more solid solid forms forms selected selected fromfrom polymorphs, polymorphs, solvates, solvates, hydrates, hydrates, and and amorphous Compound amorphous 1. Compound 1.

In some

[0072] In some

[0072] embodiments, embodiments, Compound 1 is an1 amorphous Compound solid. solid. is an amorphous FigureFigure 18 depicts the the 18 depicts X- X Raypowder Ray powder diffraction diffraction pattern pattern of of amorphous amorphous Compound Compound 1. Inembodiments, 1. In certain certain embodiments, the present the present invention provides invention providesCompound Compound 1 as 1 as an an amorphous amorphous solid substantially solid substantially free of crystalline free of crystalline

Compound Compound 1. used 1. As As used herein, herein, the "substantially the term term "substantially free offree of crystalline crystalline Compound Compound 1" means 1" means that the that the compound contains compound contains no significant no significant amount amount of crystalline of crystalline Compound Compound 1. In 1. In certain certain embodiments, embodiments, at at leastabout least 95%95% about by weight by weight of amorphous of amorphous Compound Compound 1 is present.1 is In present. In still other still other embodiments, of embodiments, of the the invention, invention, atatleast about least 99% about 99%bybyweight weightofof amorphous amorphousCompound Compound 11 is is present. present.

[0073] used herein, As herein,

[0073] As used the term any of to refers to refers term "polymorph" the"polymorph" theany of the different different crystal structures crystal structures

in which in which a acompound compoundcan can crystallize. crystallize. As herein, As used used herein, the "solvate" the term term "solvate" refers refers to a crystal to a crystal form form with either with either aa stoichiometric stoichiometricorornon-stoichiometric non-stoichiometric amount amount of solvent of solvent incorporated incorporated into into the the

1004799942

crystal structure. crystal Similarly, the structure. Similarly, the term term"hydrate" "hydrate" refersspecifically refers specificallyto toa acrystal crystalform form with with either either a a 2023206094 18 Jul 2023

stoichiometricorornon-stoichiometric stoichiometric non-stoichiometric amount amount of water of water incorporated incorporated into into the the crystal crystal structure. structure.

In certain

[0074] In certain

[0074] embodiments, embodiments, Compound Compound 1 is a1 is a crystallinesolid. crystalline solid. InInsome someembodiments, embodiments, Compound Compound 1 is1aiscrystalline a crystalline solid solid substantially substantially free free of amorphous of amorphous Compound Compound 1. As used1. herein, As used herein, the term the term "substantially "substantiallyfree of amorphous free Compound of amorphous Compound 1" 1" means that the means that thecompound contains no compound contains no

significant amount significant amount of ofamorphous amorphous Compound Compound 1.1.InIncertain certain embodiments, embodiments,atat least about 95% least about 95% by by

weightofofcrystalline weight crystalline Compound Compound 1 is present. 1 is present. In still In still otherother embodiments, embodiments, of the of the invention, invention, at at least about least 99%bybyweight about 99% weight of crystalline of crystalline Compound Compound 1 is present. 1 is present.

In some

[0075] In some

[0075] embodiments, embodiments, Compound Compound 1 is substantially freefree 1 is substantially of any of any water or or water other other

solvent. In solvent. In some someembodiments, embodiments, Compound Compound 1 is crystal 1 is a neat a neat crystal form, form, and thusand doesthus not does have not any have any water oror other water othersolvent solventincorporated incorporated into into itsitscrystal crystalstructure. structure.ItIthas hasnow now been been found found that that

Compound Compound 1 can 1 can exist exist in least in at at least oneone distinct distinct neat neat (i.e.anhydrous, (i.e. anhydrous, non-solvate) non-solvate) crystal crystal form.form.

Suchneat Such neatcrystal crystalforms formsofof Compound Compound 1 include 1 include Form I,Form Form I, Form VII, and VII, Form and Form VIII, each VIII, of each of whichisis described which describedinindetail detailherein. herein. In some

[0076] In some

[0076] embodiments, embodiments, the present the present invention invention provides provides a solvated crystalline form a solvatedcrystalline of form of

Compound Compound 1. 1.Such Such solvatedcrystalline solvated crystalline forms forms of of Compound Compound 1 1include includeForm FormIIII (DMF (DMF solvate), solvate),

FormIII Form III (DMSO solvate), Form (DMSO solvate), FormIVIV(methanol (methanolsolvate), solvate), Form FormVV(NMP (NMP solvate),and solvate), andForm FormVIVI (toluene solvate). (toluene solvate).

[0077] In some

[0077] In some embodiments, embodiments, the present the present invention invention provides provides a crystalline form of a crystalline form of Compound Compound 1 selected 1 selected from from any any of of those those referred referred to as to as I, Form Form Form I,II, Form FormII, Form III, III, Form IV,Form Form IV, Form V, Form V, FormVI,VI,Form Form VII,VII, or Form or Form VIII.VIII. Methods Methods for preparing for preparing each Iofthrough each of Forms Forms VIII I through of VIII of Compound Compound 1 aredescribed 1 are describedherein. herein. In some

[0078] In some

[0078] embodiments, embodiments, the present the present invention invention provides provides a polymorphic a polymorphic form form of of Compound Compound 1 referred 1 referred to Form to as as Form I. I.

[0079] In some

[0079] In some embodiments, embodiments, the present the present invention invention provides provides Form Form I of I of Compound Compound 1, having 1, having

a powder a X-ray powder X-ray diffraction diffraction pattern pattern substantially substantially similar similar to that to that depicted depicted in Figure in Figure 1A. 1A.

[0080] used herein, As herein,

[0080] As used the"about," the term term "about," when when used used in reference in reference to20a degree to a degree 20 value value refers refers to the to the stated stated value 0.1 degree value ± 0.1 degree20, 20,obtained obtainedunder under thethe sample sample preparation preparation and collection and data data collection conditions described conditions describedininthe theexemplification. exemplification. In some In some embodiments, embodiments, the termthe term "about," "about," when usedwhen used in reference in to aa degree reference to degree2020value valuerefers referstotothe thestated statedvalue value± 0.20.2degree degree 20.20. OneOne of skill of skill in the in the artart

will appreciate will that changes appreciate that changesininthe theparticular particularXRPD XRPD acquisition acquisition parameters parameters will affect will affect the the XRPD XRPD pattern and pattern and specific specific values valuesofofdegrees degrees20 20obtained. obtained. In some

[0081] In some

[0081] Form Form embodiments, embodiments, I of Compound I of Compound 1 is characterized 1 is characterized in that in that it it hasone has oneoror morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those in Table in Table 1 below. 1 below.

Table 1: Table 1:Compound Compound 11 Form FormII XRPD Peaks XRPD Peaks

10

1004799942

Position (°20) Position (°2) Height(cts) Height (cts) Relative Relative

2023 Intensity(%) Intensity (%)

8.73 8.73 1552 1552 6.83 6.83

2023206094 18 Jul

9.23 9.23 22736 22736 100 100

12.13 12.13 1828 1828 8.04 8.04

12.28 12.28 1818 1818 8.00 8.00

12.51 12.51 609 609 2.68 2.68

13.74 13.74 1245 1245 5.48 5.48

14.74 14.74 2776 2776 12.21 12.21

14.89 14.89 3143 3143 13.82 13.82

15.83 15.83 1881 1881 8.27 8.27

15.92 15.92 1400 1400 6.16 6.16

17.19 17.19 2164 2164 9.52 9.52

17.87 17.87 1294 1294 5.69 5.69

18.32 18.32 1466 1466 6.45 6.45

18.44 18.44 1556 1556 6.84 6.84

19.11 19.11 1171 1171 5.15 5.15

19.29 19.29 621 621 2.74 2.74

19.60 19.60 2289 2289 10.07 10.07

19.91 19.91 359 359 1.58 1.58

20.74 20.74 561 561 2.47 2.47

21.04 21.04 528 528 2.32 2.32

22.49 22.49 919 919 4.04 4.04

23.85 23.85 964 964 4.24 4.24

23.96 23.96 1534 1534 6.75 6.75

25.58 25.58 1762 1762 7.75 7.75

27.00 27.00 541 541 2.38 2.38

27.29 27.29 957 957 4.21 4.21

28.17 28.17 454 454 2.00 2.00

28.58 28.58 512 512 2.26 2.26

28.92 28.92 339 339 1.49 1.49

35.54 35.54 242 242 1.06 1.06

38.91 38.91 131 131 0.58 0.58

11

1004799942

[0082] In some

[0082] In some embodiments, Form Form embodiments, I of Compound I of Compound 1 is characterized 1 is characterized in that it it in that has twooror hastwo 2023206094 18 Jul 2023

morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those in Table in Table 1. In 1. In some some embodiments, embodiments, Form Form I of ICompound of Compound 1 is characterized 1 is characterized in that in it that it hasorthree has three moreor moreinpeaks peaks its in its powderX-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those in Table in Table 1. In 1.some In embodiments, some embodiments, Form I Form I of Compound of Compound 1 is1 characterized is characterized in that in that it has it has four four or more or more peakspeaks inpowder in its its powder X-ray X-ray diffraction diffraction

pattern selected pattern selected from fromthose thoseininTable Table 1. 1. In In some some embodiments, embodiments, Form I Form I of Compound of Compound 1 is 1 is characterizedininthat characterized that it it has has five five or or more peaksininits more peaks its powder powder X-ray X-ray diffraction diffraction pattern pattern selected selected

fromthose from thoseininTable Table1.1.InInsome some embodiments, embodiments, Form I Form I of Compound of Compound 1 is characterized 1 is characterized in that it in that it has ten has ten of of the the peaks peaksininTable Table1 1ininits its X-ray X-raydiffraction diffractionpattern. pattern.InInsome some embodiments, embodiments, Form IForm of I of Compound Compound 1 is 1characterized is characterized in that in that it has it has fifteen fifteen of of thethe peaks peaks in Table in Table 1 in1 its in its X-ray X-ray diffraction diffraction

pattern. In pattern. In some someembodiments, embodiments, Form Form I of Compound I of Compound 1 is characterized 1 is characterized in that itinhas that it hasoftwenty twenty of the peaks the in Table peaks in Table1 1ininits its X-ray X-raydiffraction diffractionpattern. pattern.InInsome some embodiments, embodiments, Form I Form of I of Compound Compound 1 is 1characterized is characterized in that in that it has it has all all of of thethe peaks peaks in Table in Table 1 in1 its in its X-ray X-ray diffraction diffraction

pattern. pattern.

In some

[0083] In some

[0083] Form Form embodiments, embodiments, I of Compound I of Compound 1 is characterized 1 is characterized in that it it in that has oneoror hasone morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those at about at about 12.51, 12.51, about about 14.89, about 14.89, about17.19, 17.19,about about19.11, 19.11,about about 19.91, 19.91, about about 28.58, 28.58, and about and about 38.91 38.91 degreesdegrees 20. 20. In some In some embodiments, embodiments, Form Form I of ICompound of Compound 1 is characterized 1 is characterized in that in it that it has has two or two more or more peaks in peaks its in its powderX-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those at about at about 12.51, 12.51, about about 14.89, 14.89, about about 17.19, 17.19, about 19.11, about 19.11,about about19.91, 19.91,about about 28.58, 28.58, and and about about 38.9138.91 degrees degrees 20. In20. someInembodiments, some embodiments, FormI IofofCompound Form Compound1 is 1characterized is characterized in that in that it has it has three three or more or more peakspeaks in its in its powder powder X-ray X-ray diffraction pattern diffraction pattern selected selected from fromthose thoseatatabout about12.51, 12.51, about about 14.89, 14.89, about about 17.19, 17.19, aboutabout 19.11,19.11,

about 19.91, about 19.91,about about28.58, 28.58,andand about about 38.91 38.91 degrees degrees 20.some 20. In In embodiments, some embodiments, Form I of Form I of Compound Compound 1 is 1characterized is characterized in that in that it has it has four four or more or more peakspeaks in itsinpowder its powder X-ray X-ray diffraction diffraction

pattern selected pattern selected from fromthose thoseatatabout about12.51, 12.51,about about 14.89, 14.89, about about 17.19, 17.19, aboutabout 19.11,19.11, about about 19.91, 19.91,

about 28.58, about 28.58, and and about about 38.91 38.91degrees degrees20. 20.InInsome someembodiments, embodiments, Form Form II of of Compound Compound 1 1isis

characterizedininthat characterized that it it has five or has five or more peaksininits more peaks its powder powder X-ray X-ray diffraction diffraction pattern pattern selected selected

fromthose from thoseatatabout about12.51, 12.51,about about 14.89, 14.89, about about 17.19, 17.19, about about 19.11, 19.11, about about 19.91,19.91, about 28.58, about 28.58, and and about38.91 about 38.91degrees degrees 20.20. In some In some embodiments, embodiments, Form Form I of I of Compound Compound 1 is characterized 1 is characterized in that it in that it has six has six or or more morepeaks peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those at about at about 12.51, 12.51,

about14.89, about 14.89,about about17.19, 17.19,about about 19.11, 19.11, about about 19.91, 19.91, aboutabout 28.58, 28.58, and about and about 38.91 degrees 38.91 degrees 20. In 20. In someembodiments, some embodiments, Form Form I of Compound I of Compound 1 is characterized 1 is characterized in that itinhas thatallit has sevenallpeaks seven in peaks its in its powder X-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom thosethose at about at about 12.51, 12.51, about about 14.89, 14.89, about 17.19, about 17.19,

about19.11, about 19.11,about about19.91, 19.91,about about 28.58, 28.58, and and about about 38.9138.91 degrees degrees 20. 20.

12

1004799942

[0084] In some

[0084] In some embodiments, Form Form embodiments, I of Compound I of Compound 1 is characterized 1 is characterized in that it it in that has oneoror hasone 2023206094 18 Jul 2023

morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those at about at about 9.2, about 9.2, about 15.8, 15.8, about 19.6, about 19.6, about about24.0, 24.0,about about25.6, 25.6,about about 28.6, 28.6, andand about about 8.7 degrees 8.7 degrees 20.some 20. In In some embodiments, embodiments,

FormI IofofCompound Form Compound1 is 1characterized is characterized in that in that it has it has twomore two or or more peaks peaks in its in its powder powder X-ray X-ray diffraction pattern diffraction pattern selected selected from fromthose thoseatatabout about9.2, 9.2,about about 15.8, 15.8, about about 19.6, 19.6, about about 24.0, 24.0, about about

25.6, about 25.6, about 28.6, 28.6, and andabout about8.78.7degrees degrees 20.20. In In some some embodiments, embodiments, Form Form I of I of Compound Compound 1 is 1 is characterizedininthat characterized that it it has has three or more three or peaksininitsitspowder more peaks powder X-ray X-ray diffraction diffraction pattern pattern selected selected

fromthose from thoseatatabout about9.2, 9.2,about about15.8, 15.8,about about 19.6, 19.6, about about 24.0, 24.0, about about 25.6, 25.6, about about 28.6,28.6, and about and about 8.7 8.7 degrees 20. degrees 20. InInsome someembodiments, embodiments, Form Form I of Compound I of Compound 1 is characterized 1 is characterized in that it in that has it has four or four or morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those at about at about 9.2, about 9.2, about 15.8, 15.8, about 19.6, about 19.6, about about24.0, 24.0,about about25.6, 25.6,about about 28.6, 28.6, andand about about 8.7 degrees 8.7 degrees 20.some 20. In In some embodiments, embodiments,

FormI IofofCompound Form Compound1 is 1characterized is characterized in that in that it has it has fivefive or more or more peakspeaks in itsinpowder its powder X-ray X-ray diffraction pattern diffraction pattern selected selected from fromthose thoseatatabout about9.2, 9.2,about about 15.8, 15.8, about about 19.6, 19.6, about about 24.0, 24.0, about about

25.6, about 25.6, about 28.6, 28.6, and andabout about8.78.7degrees degrees 20.20. In In some some embodiments, embodiments, Form Form I of I of Compound Compound 1 is 1 is characterizedininthat characterized that it it has has six six or or more peaksininits more peaks its powder powder X-ray X-ray diffraction diffraction pattern pattern selected selected

fromthose from thoseatatabout about9.2, 9.2,about about15.8, 15.8,about about 19.6, 19.6, about about 24.0, 24.0, about about 25.6, 25.6, about about 28.6,28.6, and about and about 8.7 8.7 degrees 20. degrees 20. In Insome some embodiments, FormII of embodiments, Form of Compound Compound 1 1isischaracterized characterized by by an an X-ray X-ray

diffraction pattern diffraction pattern comprising comprisingthethefollowing following peaks: peaks: about about 9.2, 9.2, about about 15.8,15.8, aboutabout 19.6, 19.6, about about 24.0, 24.0, about 25.6, about 25.6, about about28.6, 28.6,and andabout about 8.78.7 degrees degrees 20. 20.

[0085] In some

[0085] In some embodiments, embodiments, Form Form I is characterized I is characterized by by an an X-ray X-ray powder powder diffractogram diffractogram

comprisingthethefollowing comprising following peaks: peaks: 9.3,9.3, 15.0, 15.0, and and 19.8 19.8 °2 ± °20 0.2 as°20, 0.2 °20, as determined determined on a on a diffractometerusing diffractometer usingCu-K Cu-Ko radiation radiation at a wavelength at a wavelength of 1.54of Å. 1.54A. In some In some embodiments, embodiments, the the diffractogramcomprises diffractogram comprises additional additional peaks peaks at 16.0, at 16.0, 24.0, 24.0, 25.8, 25.8, and 27.3 and 27.3 °20 °2.0.2 °2 ± 0.2 °20. Compound Compound

1 Form 1 Form I Iis is also also characterized characterizedbybyitsitsX-ray X-raydiffraction diffractionpattern patternasassubstantially substantiallyshown shown in Figure in Figure

1A. Compound 1A. Compound 1 Form 1 Form I is also I is also characterized characterized by itsby its X-ray X-ray diffraction diffraction pattern pattern as substantially as substantially

shownin shown in Figure Figure 1B. 1B.

[0086] Form Form

[0086] I of Compound has been characterized 1 has been1 characterized I of Compound via single via single crystal crystal analysis the dataand andanalysis the data are summarized are summarized in Table in Table 2 and 2 and the ellipsoid the ellipsoid diagram diagram is shown is shown in Figure in Figure 2. 2. Table 2. Table 2. Crystal Crystal Data and Data Data and DataCollection Collection Parameters Parameters Empirical formula Empirical C28H31N30sS C2HNOS Formulaweight Formula weight (g (g mol-1) mol-1) 569.62 569.62

Temperature (K) Temperature (K) 293(2) 293(2)

Wavelength(Å) Wavelength (A) 1.54184 1.54184

Crystal system Crystal system orthorhombic orthorhombic

Space group Space group C2221 C2221

13

1004799942

Unit cell parameters Unit cell parameters 2023206094 18 Jul 2023

a == 14.77743(18) a 14.77743(18)AÅ a = 90° a 90° b == 14.62619(16) b 14.62619(16) Å § =90 ß = 90°

c == 51.7778(8) c 51.7778(8) Å y= 9 0° = 90°

Unit cell volume Unit cell (A3) volume (Å3) 11191.1(3) 11191.1(3)

Cell formula Cell formulaunits, units,ZZ 16 16

Calculateddensity Calculated density(g(gcm-3) cm-3) 1.352 1.352

Absorption coefficient (mm-1) Absorption coefficient (mm-1) 1.495 1.495

F(000) F(000) 4800 4800

Crystal size Crystal size (mm3) (mm3) 0.19 Xx 0.13 0.19 0.13 X x0.06 0.06 Reflectionsused Reflections usedforforcell cell 15725 15725

measurement measurement 0range rangefor cell measurement for cell measurement 3.5010°-77.2150° 3.5010°-77.2150°

Total reflections Total reflections collected collected 29754 29754 Index ranges Index ranges -18!5 h!hs18; -18 18;-14!5k k!18; s18;-63 -63 !5 /! 58 58

0range rangefor data for data collection collection 0min == 3.414°, Omin 3.414°, Omax max = =77.642° 77.642° Completeness to Completeness to Omax max 98.2% 98.2%

Completeness to Completeness Ofull == 67.684° to full 67.684° 99.7% 99.7%

Absorption correction Absorption correction multi-scan multi-scan

Transmission Transmission coefficient coefficient range range 0.918-1.000 0.918-1.000

Refinement method Refinement method full matrix full least-squares on matrix least-squares onFsqd Fsqd Independentreflections Independent reflections 11199[Rint 11199 [Rint= =0.0330, 0.0330,Ro Ra = 0.0361] = 0.0361]

Reflections[ Reflections I>2a(1)

[ I>2(I) ] ] 9830 9830

Reflections//restraints Reflections restraints // parameters parameters 11199 / 0 / 737 11199/0/737 Goodness-of-fit on Goodness-of-fit on F2 F2 S== 1.05 S 1.05 Final residuals Final residuals[[ I>2a(1)] I>2(I) ] R 0.0446, Rw R == 0.0446, 0.1187 Rw == 0.1187

Final residuals [all reflections] Final residuals [ all reflections ] R == 0.0516, R Rw == 0.1250 0.0516, Rw 0.1250 Largestdiff. Largest diff. peak andhole peak and hole(e(eÅ-3) A-3) 0.405, -0.297 0.405, -0.297

Max/meanshift/standard Max/mean shift/standard 0.001 0.001 // 0.000 0.000 uncertainty uncertainty

Absolute StructureDetermination Absolute Structure Determination Flack parameter:-0.007(8) Flack parameter: -0.007(8) Hooftparameter: Hooft parameter:-0.011(7) -0.011(7) Friedel coverage: Friedel coverage: 88.7% 88.7%

14

1004799942

In some

[0087] In some

[0087] embodiments, Form Form embodiments, I of Compound I of Compound 1 is characterized by a by 1 is characterized a differential differential 2023206094 18 Jul 2023

scanningcalorimetry scanning calorimetry (DSC) (DSC) curve curve that that comprises comprises an endotherm an endotherm between between about 189 about 189 °C to about C to about 193 °C.C. Form 193 FormI of I ofCompound Compound 1 is also 1 is also characterized characterized by itsby itscurve DSC DSCascurve as substantially substantially shown inshown in Figure 3A. Figure 3A.InInsome some embodiments, embodiments, Form IForm I of Compound of Compound 1 is also characterized 1 is also characterized by its DSC by its curve DSC curve as substantially as shownininFigure substantially shown Figure 3B.3B.

[0088] In some

[0088] In some embodiments, embodiments, Form Form I of Compound I of Compound 1 is characterized 1 is characterized by a by a thermogravimetric thermogravimetric analysis analysis (TGA) (TGA) curvecurve as substantially as substantially shown shown in in 4A. Figure Figure 4A. In some In some embodiments, Form embodiments, FormI IofofCompound Compound 1 ischaracterized 1 is characterized by by aa thermogravimetric thermogravimetric analysis analysis (TGA) (TGA)

curve asas substantially curve substantially shown shownin in Figure Figure 4B.4B.

[00891

[0089] In some In some embodiments, least about embodiments, atat least about95% weight of by weight 95% by of Form I of Form I Compound 11 is of Compound is present. InInsome present. someembodiments, embodiments, at least at least aboutabout 99% 99% by by weight weight of Form of Form I of I of Compound Compound 1 is 1 is present. present.

In some

[0090] In some

[0090] embodiments, embodiments, the crystalline the crystalline form is is form least about 85% atatleast of Form 85% of FormI. In some I. In some

embodiments, embodiments, thethe crystalline crystalline form form is least is at at least about about 90% 90% of Form of Form I. In I. In embodiments, some some embodiments, the the crystalline form crystalline formisis at at least least about 95%ofofForm about 95% Form I. I. In In some some embodiments, embodiments, the crystalline the crystalline form isform at is at least about least 99%ofofForm about 99% Form I. In I. In some some embodiments, embodiments, the crystalline the crystalline form isform is at about at least least about 99.5% 99.5% of of FormI.I. InIn some Form someembodiments, embodiments, the crystalline the crystalline form form is at is at least least aboutabout 99.9%99.9% of Formof I.Form I. In In some some embodiments, embodiments, thethe crystalline crystalline form form is least is at at least about about 99.99% 99.99% of Form of Form I. I.

[0091] SomeSome

[0091] embodiments embodiments provide provide for a for a pharmaceutical pharmaceutical composition composition comprising comprising

Compound Compound 1 inForm 1 in FormI.I.In In one one embodiment, embodiment,the thepharmaceutical pharmaceutical composition compositioncomprises comprises Compound Compound 1 whereinat atleast 1 wherein least about about 85% 85%ofofCompound Compound 1 isininForm 1 is FormI.I. In In one one embodiment, the embodiment, the

pharmaceutical composition pharmaceutical composition comprises comprises Compound Compound 1 wherein 1 wherein at at least about least about 90% 90%ofofCompound Compound1 1 is ininForm is FormI.I. InIn oneone embodiment, embodiment,the pharmaceutical the pharmaceuticalcomposition compositioncomprises comprisesCompound Compound 11

whereinatatleast wherein least about 95% about95% of of Compound Compound 1 is in1 Form is in I.Form I. In In one one embodiment, embodiment, the pharmaceutical the pharmaceutical

composition comprises composition comprises Compound Compound 1wherein 1 wherein at at least about least 99%ofofCompound about 99% Compound1 is1 is ininForm FormI.I.In In one embodiment, one embodiment, the the pharmaceutical pharmaceutical composition composition comprises comprises Compound Compound 1 wherein 1 wherein at at leastabout least about 99.5% of 99.5% of Compound Compound 1 isininForm 1 is FormI. I. In In one one embodiment, the pharmaceutical embodiment, the pharmaceutical composition composition comprises Compound comprises Compound 1 wherein 1 wherein at atleast least about about 99.9% 99.9%ofofCompound Compound 1 isininForm 1 is FormI.I. In In one one

embodiment, the embodiment, the pharmaceutical pharmaceutical composition composition comprises comprises Compound Compound 1 wherein 1 wherein at at leastabout least about 99.99%ofofCompound 99.99% Compound 1 isininForm 1 is FormI.I. In some

[0092] In some

[0092] embodiments, embodiments, the present the present invention invention provides provides a solvated crystalline form a solvatedcrystalline of form of

Compound Compound 1 referred 1 referred to Form to as as Form II.some II. In In some embodiments, embodiments, theinvention the present present invention provides provides Form Form II of II of Compound 1, having Compound 1, having a powder a powder X-ray X-ray diffraction diffraction patternpattern substantially substantially similarsimilar to thatto that depicted inin Figure depicted Figure5.5.InInsome some embodiments, embodiments, Form Form II II of Compound of Compound 1 is characterized 1 is characterized in that it in that it

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has one has oneorormore morepeaks peaks in in itsits powder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those in Table in Table 3 3 2023206094 18 Jul 2023

below. below.

Table 3.3. Compound Table Compound 11 Form FormII 1 XRPD XRPDPeaks Peaks Position (°20) Position (°2) Height (cts) Height (cts) Relative Relative

Intensity(%) Intensity (%)

7.56 7.56 124.9 124.9 57.7 57.7

8.09 8.09 137.8 137.8 63.7 63.7

9.18 9.18 77.0 77.0 35.6 35.6

11.34 11.34 34.6 34.6 16.0 16.0

11.74 11.74 75.6 75.6 35.0 35.0

12.21 12.21 51.9 51.9 24.0 24.0

12.80 12.80 35.1 35.1 16.2 16.2

14.37 14.37 31.6 31.6 14.6 14.6

15.38 15.38 96.4 96.4 44.6 44.6

15.80 15.80 28.8 28.8 13.3 13.3

17.01 17.01 50.8 50.8 23.5 23.5

17.56 17.56 30.2 30.2 14.0 14.0

18.30 18.30 20.3 20.3 9.4 9.4

19.56 19.56 216.3 216.3 100.0 100.0

20.67 20.67 28.6 28.6 13.2 13.2

21.00 21.00 50.3 50.3 23.2 23.2

22.77 22.77 128.2 128.2 59.3 59.3

23.00 23.00 44.7 44.7 20.7 20.7

23.29 23.29 73.6 73.6 34.0 34.0

25.62 25.62 159.8 159.8 73.9 73.9

26.23 26.23 14.2 14.2 6.6 6.6

27.05 27.05 30.4 30.4 14.0 14.0

28.92 28.92 31.5 31.5 14.6 14.6

[0093]

[0093] In someembodiments, In some embodiments,Form Form II of Compound II of Compound 1 is characterized thattwo in that itinhas 1 is characterized or two or it has morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those in Table in Table 3. In 3. In some some embodiments, embodiments, Form Form II ofIICompound of Compound 1 is characterized 1 is characterized in that in it that it has or has three three moreor moreinpeaks peaks its in its powderX-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those in Table in Table 3. In 3.some In embodiments, some embodiments, Form II Form II of Compound of Compound 1 is1 characterized is characterized in that in that it has it has four four or more or more peaks peaks inpowder in its its powder X-ray X-ray diffraction diffraction

16

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pattern selected pattern selected from fromthose thoseininTable Table 3. 3. In In some some embodiments, embodiments, Form IIForm II of Compound of Compound 1 is 1 is 2023206094 18 Jul 2023

characterizedininthat characterized that it it has has five five or or more peaksininits more peaks its powder powder X-ray X-ray diffraction diffraction pattern pattern selected selected

fromthose from thoseininTable Table3.3.InInsome some embodiments, embodiments, Form IIForm II of Compound of Compound 1 is characterized 1 is characterized in that it in that it has all has all of of the the peaks in Table peaks in Table33 inin its its X-ray diffraction pattern. X-ray diffraction pattern.

[0094]

[0094] In In some Form Form embodiments, someembodiments, II of Compound II of Compound 1 is characterized in that itinhas 1 is characterized thatone or one or it has morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those 7.56, 7.56, at about at about about about 8.09, 8.09, about 11.34, about 11.34,about about11.74, 11.74,about about 14.37, 14.37, about about 15.38, 15.38, aboutabout 17.56,17.56, and about and about 23.00 degrees 23.00 degrees 20. In 20. In someembodiments, some embodiments, Form Form II of Compound II of Compound 1 is characterized 1 is characterized in that itinhas thattwoit has twopeaks or more or more in peaks in its powder its X-raydiffraction powder X-ray diffractionpattern patternselected selected from from those those at about at about 7.56, 7.56, about about 8.09,8.09, aboutabout 11.34,11.34,

about 11.74, about 11.74,about about14.37, 14.37,about about 15.38, 15.38, about about 17.56, 17.56, and about and about 23.00 23.00 degreesdegrees 20. In 20. some In some embodiments, embodiments, Form Form II ofIICompound of Compound 1 is characterized 1 is characterized in that in it that it has orthree has three moreor moreinpeaks peaks its in its powderX-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those at about at about 7.56,7.56, aboutabout 8.09, 8.09, about about 11.34, 11.34,

about 11.74, about 11.74,about about14.37, 14.37,about about 15.38, 15.38, about about 17.56, 17.56, and about and about 23.00 23.00 degreesdegrees 20. In 20. some In some embodiments, embodiments, Form Form II ofIICompound of Compound 1 is characterized 1 is characterized in that in it that it hasorfour has four moreor moreinpeaks peaks its in its powderX-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those at about at about 7.56,7.56, aboutabout 8.09, 8.09, about about 11.34, 11.34,

about 11.74, about 11.74,about about14.37, 14.37,about about 15.38, 15.38, about about 17.56, 17.56, and about and about 23.00 23.00 degreesdegrees 20. In 20. some In some embodiments, embodiments, Form Form II ofIICompound of Compound 1 is characterized 1 is characterized in that in it that it hasorfive has five moreorpeaks moreinpeaks its in its powderX-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those at about at about 7.56,7.56, aboutabout 8.09, 8.09, about about 11.34, 11.34,

about 11.74, about 11.74,about about14.37, 14.37,about about 15.38, 15.38, about about 17.56, 17.56, and about and about 23.00 23.00 degreesdegrees 20. In 20. some In some embodiments, embodiments, Form Form II ofIICompound of Compound 1 is characterized 1 is characterized in that in it that it has has six or six moreor moreinpeaks peaks its in its powderX-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those at about at about 7.56,7.56, aboutabout 8.09, 8.09, about about 11.34, 11.34,

about 11.74, about 11.74,about about14.37, 14.37,about about 15.38, 15.38, about about 17.56, 17.56, and about and about 23.00 23.00 degreesdegrees 20. In 20. some In some embodiments, embodiments, Form Form II ofIICompound of Compound 1 is characterized 1 is characterized in that in it that it has orseven has seven more or more peaks in peaks its in its powderX-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those at about at about 7.56,7.56, aboutabout 8.09, 8.09, about about 11.34, 11.34,

about 11.74, about 11.74,about about14.37, 14.37,about about 15.38, 15.38, about about 17.56, 17.56, and about and about 23.00 23.00 degreesdegrees 20. In 20. some In some embodiments, embodiments, Form Form II ofIICompound of Compound 1 is characterized 1 is characterized in that in it that it has has all all peaks eight eight in peaks its in its powder powder

X-raydiffraction X-ray diffractionpattern patternselected selectedfrom from those those at at about about 7.56, 7.56, about about 8.09, 8.09, about about 11.34, 11.34, aboutabout 11.74,11.74,

about 14.37, about 14.37,about about15.38, 15.38,about about 17.56, 17.56, and and about about 23.0023.00 degrees degrees 20. 20. In some

[0095] In some

[0095] embodiments, embodiments, II of II Form Form of Compound Compound 1 is characterized 1 is characterized in that it ithas in that oneoror hasone morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those at about at about 12.2, about 12.2, about 12.8, 12.8, about 17.0, about 17.0, about about19.6, 19.6,about about21.0, 21.0,andand about about 22.822.8 degrees degrees 20. 20. In some

[0096] In some

[0096] embodiments, embodiments, the present the present invention invention provides provides a solvated crystalline form a solvatedcrystalline of form of

Compound Compound 1 referred 1 referred to Form to as as Form III. III. In some In some embodiments, embodiments, theinvention the present present invention provides provides FormIII Form IIIofofCompound Compound 1, having 1, having a powder a powder X-ray diffraction X-ray diffraction pattern pattern substantially substantially similar similar to that to that depicted inin Figure depicted Figure6.6. InInsome some embodiments, embodiments, Form Form III III of Compound of Compound 1 is characterized 1 is characterized in that it in that it

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has one has oneorormore morepeaks peaks in in itsits powder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those in Table in Table 4 4 2023206094 18 Jul 2023

below. below.

Table 4. Table 4.Compound Compound 11 Form II XRPD Form III Peaks XRPD Peaks

Position (°20) Position (°2) Height (cts) Height (cts) Relative Relative

Intensity(%) Intensity (%)

6.27 6.27 38.8 38.8 27.5 27.5

7.95 7.95 51.2 51.2 20.5 20.5

8.10 8.10 67.3 67.3 26.9 26.9

8.50 8.50 153.5 153.5 61.4 61.4

9.16 9.16 21.4 21.4 8.6 8.6

12.18 12.18 250.2 250.2 100.0 100.0

15.76 15.76 114.7 114.7 45.8 45.8

15.88 15.88 227.1 227.1 90.8 90.8

17.89 17.89 18.7 18.7 7.5 7.5

18.02 18.02 38.7 38.7 15.5 15.5

21.61 21.61 61.2 61.2 24.5 24.5

23.27 23.27 42.9 42.9 17.1 17.1

23.78 23.78 39.1 39.1 15.6 15.6

24.14 24.14 41.3 41.3 16.5 16.5

26.00 26.00 33.3 33.3 13.3 13.3

26.21 26.21 28.0 28.0 11.2 11.2

[0097]

[0097] In someembodiments, In some embodiments,Form Form III ofIII of Compound Compound 1 is characterized 1 is characterized in has in that it thattwo or two or it has morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those in Table in Table 4. In 4. In some some embodiments, embodiments, Form Form IIICompound III of of Compound 1 is characterized 1 is characterized in that in it that it has or has three three moreor moreinpeaks peaks its in its powder X-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those in Table in Table 4. In 4.some In embodiments, some embodiments, Form Form III of III of Compound Compound 1 is1 characterized is characterized in that in that it it hashas four four or or more more peaks peaks in powder in its its powder X-rayX-ray

diffraction pattern diffraction pattern selected selected from fromthose thoseininTable Table 4. 4. In In some some embodiments, embodiments, Form Form III of III of Compound Compound 1 is 1characterized is characterized in that in that it has it has five five or or more more peaks peaks in powder in its its powder X-ray X-ray diffraction diffraction

pattern selected from pattern selected fromthose thoseininTable Table 4. 4. In In some some embodiments, embodiments, Form Form III III of Compound of Compound 1 is 1 is characterizedininthat characterized that it it has has all all of of the the peaks in in peaks in in Table Table 44 in in its its X-ray diffraction pattern. X-ray diffraction pattern.

[0098]

[0098] In In some embodiments, someembodiments, III ofIII Form Form of Compound Compound 1 is characterized 1 is characterized in has in that it thatone or one or it has morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those at about at about 6.27, 6.27, about about 18.02, about 18.02, about 21.61, 21.61,and andabout about24.14 24.14degrees 20.20.InIn degrees some someembodiments, embodiments,Form Form III IIIofofCompound Compound

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1 is 1 is characterized in that characterized in that it ithas has two two or or more peaksininits more peaks its powder powder X-ray X-ray diffraction diffraction pattern pattern

6.27,about 2023206094 18 Jul 2023

selected from selected fromthose thoseatatabout about6.27, about 18.02, 18.02, about about 21.61, 21.61, and about and about 24.14 24.14 degrees degrees 20. In 20. In someembodiments, some embodiments,Form Form III ofIII of Compound Compound 1 is characterized 1 is characterized inhas in that it thatthree it hasorthree more or more peaks peaks in its in itspowder X-raydiffraction powder X-ray diffractionpattern patternselected selectedfrom from those those at about at about 6.27, 6.27, about about 18.02, 18.02, aboutabout

21.61, and 21.61, and about about 24.14 24.14 degrees degrees20. 20.In Insome some embodiments, embodiments, Form III of Form III of Compound Compound 1 1is is characterizedininthat characterized that it it has has all all four four peaks in its peaks in its powder X-raydiffraction powder X-ray diffractionpattern patternselected selected from from

those at those at about about 6.27, 6.27, about about18.02, 18.02,about about 21.61, 21.61, andand about about 24.14 24.14 degrees degrees 20. 20. In some

[0099] In some

[0099] Form Form embodiments, embodiments, III of of Compound IIICompound 1 is characterized 1 is characterized in that it ithas in that oneoror hasone morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those at about at about 6.3, about 6.3, about 8.5, 8.5, about 12.2, about 12.2, about about15.9, 15.9,and andabout about 21.6 21.6 degrees degrees 20. 20. In some

[0100] In some

[0100] embodiments, embodiments, the present the present invention invention provides provides a solvated crystalline form a solvatedcrystalline of form of

Compound Compound 1 referred toto as 1 referred as Form IV. In Form IV. In some someembodiments, embodiments,the thepresent present invention invention provides provides

FormIVIVof of Form Compound Compound 1, having 1, having a powder a powder X-ray diffraction X-ray diffraction pattern substantially pattern substantially similar tosimilar that to that depicted inin Figure depicted Figure7A. 7A.InInsome some embodiments, embodiments, the present the present invention invention providesprovides Form Form IV of IV of Compound Compound 1, having 1, having a powder a powder X-ray X-ray diffraction diffraction patternpattern substantially substantially similar similar to that to that depicted depicted in in Figure 7B. Figure 7B.InInsome some embodiments, embodiments, Form Form IV IV of Compound of Compound 1 is characterized 1 is characterized in that in that it has it one or has one or morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those listedlisted in Table in Table 5 below. 5 below.

Table 5.5.Compound Table Compound 11 Form IV XRPD Form IV XRPDPeaks Peaks Position (°20) Position (°2) Height(cts) Height (cts) Relative Relative

Intensity(%) Intensity (%)

8.60 8.60 18.2 18.2 4.2 4.2

8.73 8.73 19.6 19.6 4.5 4.5

9.73 9.73 147.8 147.8 34.0 34.0

9.88 9.88 435.1 435.1 100 100

10.56 10.56 183.9 183.9 42.3 42.3

10.70 10.70 127.6 127.6 29.3 29.3

11.86 11.86 107.8 107.8 24.8 24.8

11.97 11.97 58.2 58.2 13.4 13.4

13.50 13.50 139.5 139.5 32.1 32.1

14.54 14.54 126.5 126.5 29.1 29.1

15.80 15.80 29.7 29.7 6.8 6.8

16.46 16.46 19.2 19.2 4.4 4.4

16.62 16.62 41.5 41.5 9.5 9.5

17.74 17.74 46.1 46.1 10.6 10.6

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19.30 19.30 120.7 120.7 27.7 27.7 2023206094 18 Jul 2023

20.36 20.36 253.3 253.3 58.2 58.2

21.30 21.30 24.6 24.6 5.7 5.7

21.94 21.94 385.6 385.6 88.6 88.6

23.90 23.90 30.7 30.7 7.1 7.1

25.61 25.61 55.5 55.5 12.8 12.8

26.72 26.72 405.3 405.3 93.2 93.2

28.28 28.28 41.3 41.3 9.5 9.5

29.02 29.02 43.2 43.2 9.9 9.9

In some

[0101] In some

[0101] embodiments, embodiments, IV of IV Form Form of Compound Compound 1 is characterized 1 is characterized in that in that it hastwotwo it has or or

morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those in Table in Table 5. In 5. In some some embodiments, embodiments, Form Form IV ofIV of Compound Compound 1 is characterized 1 is characterized in has in that it thatthree it hasorthree more or more peaks in peaks its in its powderX-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those in Table in Table 5. In 5.some In embodiments, some embodiments, Form Form IV of IV ofCompound Compound1 is 1characterized is characterized in that in that it has it has fourfour or more or more peakspeaks in itsinpowder its powder X-ray X-ray diffraction pattern diffraction pattern selected selected from fromthose thoseininTable Table 5. 5. In In some some embodiments, embodiments, Form IVForm of IV of Compound Compound 1 is 1characterized is characterized in that in that it has it has five five or or more more peaks peaks in powder in its its powder X-ray X-ray diffraction diffraction

pattern selected pattern selected from fromthose thoseininTable Table 5. 5. In In some some embodiments, embodiments, Form IVForm IV of Compound of Compound 1 is 1 is characterizedininthat characterized that it it has has all all of of the the peaks in Table peaks in Table 55 in in its its X-ray diffraction pattern. X-ray diffraction pattern.

[0102] In some

[0102] In some embodiments, IV of IV Form Form embodiments, of Compound Compound 1 is characterized 1 is characterized in that in that it has it has oneoror one

morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those at about at about 9.73, 9.73, about about 9.88, 9.88, about10.56, about 10.56,about about10.70, 10.70,about about 11.86, 11.86, about about 11.97, 11.97, aboutabout 14.54,14.54, about about 16.62, 16.62, about 21.30, about 21.30, about about 21.94, and 21.94, and about about 26.72 26.72 degrees degrees20. 20. In Insome some embodiments, embodiments, Form IV of Form IV of Compound Compound 1 is 1 is

characterizedininthat characterized that it it has has two or more two or morepeaks peaks in in itsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected

fromthose from thoseatatabout about9.73, 9.73,about about 9.88,about 9.88, about 10.56, 10.56, about about 10.70, 10.70, aboutabout 11.86,11.86, about about 11.97, 11.97, about about 14.54, about 14.54, about16.62, 16.62,about about21.30, 21.30,about about 21.94, 21.94, and and about about 26.7226.72 degrees degrees 20. In20. someIn some embodiments, embodiments, Form Form IV ofIV of Compound Compound 1 is characterized 1 is characterized in has in that it thatthree it hasorthree more or more peaks in peaks its in its powderX-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those at about at about 9.73,9.73, aboutabout 9.88, 9.88, about about 10.56, 10.56,

about 10.70, about 10.70,about about11.86, 11.86,about about 11.97, 11.97, about about 14.54, 14.54, aboutabout 16.62,16.62, about about 21.30,21.30, about 21.94, about 21.94, and and about 26.72 about 26.72degrees degrees20.20.In some In some embodiments, embodiments, Form IVForm IV of Compound of Compound 1 is characterized 1 is characterized in that in that it has it has four four or or more peaksininits more peaks its powder powder X-ray X-ray diffraction diffraction pattern pattern selected selected fromfrom thosethose at about at about

9.73, about 9.73, about 9.88, 9.88, about about10.56, 10.56,about about 10.70, 10.70, about about 11.86, 11.86, about about 11.97, 11.97, aboutabout 14.54,14.54, about about 16.62, 16.62, about 21.30, about 21.30, about about 21.94, 21.94,and andabout about26.72 26.72degrees 20.20.InIn degrees some someembodiments, embodiments, Form Form IV IV of of

Compound Compound 1 is 1characterized is characterized in that in that it has it has five five or or more more peaks peaks in powder in its its powder X-ray X-ray diffraction diffraction

pattern selected from pattern selected fromthose thoseatatabout about 9.73,about 9.73, about 9.88, 9.88, about about 10.56, 10.56, about about 10.70, 10.70, aboutabout 11.86,11.86,

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about 11.97, about 11.97,about about14.54, 14.54, about about 16.62, 16.62, about about 21.30, 21.30, aboutabout 21.94, 21.94, and about and about 26.72 degrees 26.72 degrees 20. In 20. In 2023206094 18 Jul 2023

someembodiments, some embodiments, Form Form IV of IV of Compound Compound 1 is characterized 1 is characterized in that it in that has sixitor hasmore sixpeaks or more in peaks in its powder its X-raydiffraction powder X-ray diffractionpattern patternselected selected from from those those at about at about 9.73, 9.73, about about 9.88,9.88, aboutabout 10.56,10.56,

about 10.70, about 10.70,about about11.86, 11.86,about about 11.97, 11.97, about about 14.54, 14.54, aboutabout 16.62,16.62, about about 21.30,21.30, about 21.94, about 21.94, and and about 26.72 about 26.72degrees degrees20.20.In some In some embodiments, embodiments, Form IVForm IV of Compound of Compound 1 is characterized 1 is characterized in that in that it has it has seven or more seven or morepeaks peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from thosethose at about at about

9.73, about 9.73, about 9.88, 9.88, about about10.56, 10.56,about about 10.70, 10.70, about about 11.86, 11.86, about about 11.97, 11.97, aboutabout 14.54,14.54, about about 16.62, 16.62, about 21.30, about 21.30, about about21.94, 21.94,and andabout about26.72 26.72degrees 20.20.InIn degrees some someembodiments, embodiments,Form Form IV IV of of

Compound Compound 1 is 1characterized is characterized in that in that it has it has nine nine or more or more peakspeaks in itsinpowder its powder X-ray X-ray diffraction diffraction

pattern selected pattern selected from fromthose thoseatatabout about 9.73,about 9.73, about 9.88, 9.88, about about 10.56, 10.56, about about 10.70, 10.70, aboutabout 11.86,11.86,

about 11.97, about 11.97,about about14.54, 14.54,about about 16.62, 16.62, about about 21.30, 21.30, aboutabout 21.94, 21.94, and about and about 26.72 degrees 26.72 degrees 20. In 20. In someembodiments, some embodiments, Form Form IV of IV of Compound Compound 1 is characterized 1 is characterized in that it in that has tenitor hasmore tenpeaks or more in peaks in its powder its X-raydiffraction powder X-ray diffractionpattern patternselected selected from from those those at about at about 9.73, 9.73, about about 9.88,9.88, aboutabout 10.56,10.56,

about 10.70, about 10.70,about about11.86, 11.86,about about 11.97, 11.97, about about 14.54, 14.54, aboutabout 16.62,16.62, about about 21.30,21.30, about 21.94, about 21.94, and and about 26.72 about 26.72degrees degrees20.20.In some In some embodiments, embodiments, Form IVForm IV of Compound of Compound 1 is characterized 1 is characterized in that in that it has it has all alleleven eleven peaks in its peaks in its powder X-raydiffraction powder X-ray diffractionpattern patternselected selected from from those those at about at about 9.73, 9.73,

about 9.88, about 9.88, about about10.56, 10.56,about about 10.70, 10.70, about about 11.86, 11.86, about about 11.97, 11.97, aboutabout 14.54,14.54, about 16.62, about 16.62, about about 21.30, about 21.30, about21.94, 21.94,and andabout about 26.72 26.72 degrees degrees 20. 20.

[0103] In some

[0103] In some embodiments, IV of IV Form Form embodiments, of Compound Compound 1 is characterized 1 is characterized in that in that it has it has one oror one morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those at about at about 9.9, about 9.9, about 10.6, 10.6, about11.9, about 11.9, about about14.5, 14.5,about about 16.6,about 16.6, about 21.9, 21.9, andand about about 26.7 26.7 degrees degrees 20. 20.

[0104] In some

[0104] In some embodiments, IV of IV Form Form embodiments, of Compound Compound 1 is characterized by anby 1 is characterized an X-ray X-ray powder powder

diffractogramcomprising diffractogram comprising the the following following peaks: peaks: 9.9, 9.9, 10.7,10.7, 19.5, 19.5, 22.0,22.0, and °20 and 26.8 26.8± °20 0.2as°20, 0.2 °20, as determinedonon determined a diffractometer a diffractometer using using Cu-KCu-Kc radiation radiation at a wavelength at a wavelength ofThe of 1.54 Å. 1.54 A. The diffractogramcomprises diffractogram comprises additional additional peaks peaks at 8.7, at 8.7, 12.0, 12.0, and and 14.7 14.7 °20 ±°20 0.2 Compound 0.2 °20. °20. Compound 1 1 FormIVIVis isalso Form alsocharacterized characterized by by its its X-ray X-ray diffraction diffraction pattern pattern as substantially as substantially shown shown in Figure in Figure

7A. Compound 7A. Compound 1 Form 1 Form IV is IV alsoischaracterized also characterized by its by its diffraction X-ray X-ray diffraction pattern pattern as substantially as substantially

shownin shown in Figure Figure 7B. 7B.

In some

[0105] In some

[0105] embodiments, embodiments, IV of IV Form Form of Compound Compound 1 is characterized by a by 1 is characterized a differential differential

scanningcalorimetry scanning calorimetry (DSC) (DSC) curve curve that that comprises comprises an endotherms an endotherms at 85 andat190 85 and and202 190°Cand and 202 °C and exothermatat146146°C.°C. exotherm Form Form IV ofIV of Compound Compound 1 is also1 characterized is also characterized bycurve by its DSC its DSC as curve as substantially shown substantially shownininFigure Figure 8. 8.

[0106] In some

[0106] In some embodiments, embodiments, Form Form IV of IV of Compound Compound 1 is characterized 1 is characterized by a by a thermogravimetric thermogravimetric analysis analysis (TGA) (TGA) curve curve as substantially as substantially shown shown in in 9. Figure Figure 9.

21

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[0107]

[0107] In In some embodiments, someembodiments, the present the present invention invention provides provides a solvated a solvated crystalline form ofform of crystalline 2023206094 18 Jul 2023

Compound Compound 1 referred toto as 1 referred as Form V. InIn some Form V. someembodiments, embodiments,thethepresent presentinvention invention provides provides Form Form

VofofCompound V Compound 1, having 1, having a powder a powder X-ray diffraction X-ray diffraction pattern pattern substantially substantially similar similar to that to that depicted inin Figure depicted Figure10. 10.InInsome some embodiments, embodiments, Form V Form V of Compound of Compound 1 is characterized 1 is characterized in that it in that it has one has oneorormore morepeaks peaks in in itsits powder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those in Table in Table 6 6 below. below.

Table 6.6.Compound Table Compound 11 Form Form VV XRPD XRPDPeaks Peaks Position (°20) Position (°2) Height(cts) Height (cts) Relative Relative

Intensity(%) Intensity (%)

5.85 5.85 16.3 16.3 9 9

8.03 8.03 98.6 98.6 52 52

8.23 8.23 70.0 70.0 37 37

11.02 11.02 47.7 47.7 25 25

11.15 11.15 24.2 24.2 13 13

12.69 12.69 104.3 104.3 55 55

13.34 13.34 85.9 85.9 45 45

13.50 13.50 77.2 77.2 41 41

15.68 15.68 22.3 22.3 12 12

16.23 16.23 75.1 75.1 40 40

16.28 16.28 37.2 37.2 20 20

16.51 16.51 92.8 92.8 49 49

17.32 17.32 14.6 14.6 8 8

17.87 17.87 24.0 24.0 13 13

18.93 18.93 26.0 26.0 14 14

20.29 20.29 47.2 47.2 25 25

20.69 20.69 69.6 69.6 37 37

22.66 22.66 189.4 189.4 100 100

23.47 23.47 45.9 45.9 24 24

24.56 24.56 27.3 27.3 14 14

25.40 25.40 33.4 33.4 18 18

26.08 26.08 40.3 40.3 21 21

[0108]

[0108] In embodiments, someembodiments, In some Form Form V of Compound V of Compound 1 is characterized in that it in 1 is characterized has twoitor that has two or morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those in Table in Table 6. In 6. In some some

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embodiments, embodiments, Form Form V of V of Compound Compound 1 is characterized 1 is characterized inhas in that it thatthree it hasorthree more or more peaks in peaks its in its 2023206094 18 Jul 2023

powderX-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those in Table in Table 6. In 6.some In embodiments, some embodiments, Form V Form V of Compound of Compound 1 is1 characterized is characterized in that in that it has it has fourfour or more or more peakspeaks inpowder in its its powder X-ray X-ray diffraction diffraction

pattern selected pattern selectedfrom fromthose thosein in Table 6. 6. Table In some embodiments, In some embodiments,Form FormVV of ofCompound Compound 11 is is characterizedininthat characterized that it it has has five five or or more peaksininits more peaks its powder powder X-ray X-ray diffraction diffraction pattern pattern selected selected

fromthose from thoseininTable Table6.6.InInsome some embodiments, embodiments, Form V Form V of Compound of Compound 1 is characterized 1 is characterized in that it in that it has all has all of of the the peaks in Table peaks in Table66ininits its X-ray diffraction pattern. X-ray diffraction pattern.

[0109] In some

[0109] In some embodiments, Form Form embodiments, V of Compound V of Compound 1 is characterized 1 is characterized in that in that it has oneone it has or or

morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those at about at about 5.85, 5.85, about about 8.23, 8.23, about 11.02, about 11.02,about about11.15, 11.15,about about 12.69, 12.69, about about 13.34, 13.34, aboutabout 16.23,16.23, about about 16.28, 16.28, about about about 17.32, 17.32, about 18.93, about 18.93, about23.47, 23.47,about about24.56, 24.56, andand about about 25.40 25.40 degrees degrees 20.someIn embodiments, 20. In some embodiments, Form V of Form V of Compound Compound 1 is 1characterized is characterized in that in that it has it has twotwo or more or more peakspeaks in itsinpowder its powder X-ray diffraction X-ray diffraction

pattern selected pattern selected from fromthose thoseatatabout about 5.85,about 5.85, about 8.23, 8.23, about about 11.02, 11.02, about about 11.15, 11.15, aboutabout 12.69,12.69,

about 13.34, about 13.34,about about16.23, 16.23,about about 16.28, 16.28, about about 17.32, 17.32, aboutabout 18.93,18.93, about about 23.47,23.47, about 24.56, about 24.56, and and about 25.40 about 25.40 degrees degrees 20. 20. In In some some embodiments, FormV VofofCompound embodiments, Form Compound 1 is 1 is characterizedininthat characterized that it has it has three three or or more peaksininits more peaks its powder powderX-ray X-ray diffraction diffraction pattern pattern selected selected fromfrom thosethose at about at about

5.85, about 5.85, about 8.23, 8.23, about about11.02, 11.02,about about 11.15, 11.15, about about 12.69, 12.69, about about 13.34, 13.34, aboutabout 16.23,16.23, about about 16.28, 16.28, about 17.32, about 17.32,about about18.93, 18.93,about about 23.47, 23.47, about about 24.56, 24.56, and about and about 25.40 25.40 degreesdegrees 20. In 20. some In some embodiments, embodiments, Form Form V of V of Compound Compound 1 is characterized 1 is characterized inhas in that it thatfour it has or four or more more peaks peaks in its in its powderX-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those at about at about 5.85,5.85, aboutabout 8.23, 8.23, about about 11.02, 11.02,

about 11.15, about 11.15,about about12.69, 12.69,about about 13.34, 13.34, about about 16.23, 16.23, aboutabout 16.28,16.28, about about 17.32, 17.32, about about about 18.93, 18.93, about 23.47, about 23.47, about 24.56, 24.56,and andabout about25.40 25.40degrees degrees20.20.InIn some someembodiments, embodiments, Form Form V of Compound V of Compound 1 1

is characterized is in that characterized in that it it has has five five or or more peaksininits more peaks its powder X-ray powder X-ray diffraction diffraction pattern pattern selected selected

fromthose from thoseatatabout about5.85, 5.85,about about 8.23,about 8.23, about 11.02, 11.02, about about 11.15, 11.15, aboutabout 12.69,12.69, about about 13.34, 13.34, about about 16.23, about 16.23, about16.28, 16.28,about about17.32, 17.32,about about 18.93, 18.93, about about 23.47, 23.47, aboutabout 24.56, 24.56, and 25.40 and about about degrees 25.40 degrees 20. InIn some 20. someembodiments, embodiments, Form Form V of Compound V of Compound 1 is characterized 1 is characterized in that in that it has six it orhas six more or more peaks in its peaks in its powder X-ray powder X-ray diffraction diffraction pattern pattern selected selected from from those those at about at about 5.85,5.85, aboutabout 8.23, 8.23, about about

11.02, about 11.02, about11.15, 11.15,about about12.69, 12.69,about about 13.34, 13.34, about about 16.23, 16.23, aboutabout 16.28,16.28, about about 17.32, 17.32, about about 18.93, about 18.93, about23.47, 23.47,about about24.56, 24.56, andand about about 25.40 25.40 degrees degrees 20.someIn embodiments, 20. In some embodiments, Form V of Form V of Compound Compound 1 is 1characterized is characterized in that in that it has it has seven seven or more or more peakspeaks in itsin its powder powder X-ray diffraction X-ray diffraction

pattern selected from pattern selected fromthose thoseatatabout about 5.85,about 5.85, about 8.23, 8.23, about about 11.02, 11.02, about about 11.15, 11.15, aboutabout 12.69,12.69,

about13.34, about 13.34,about about16.23, 16.23,about about 16.28, 16.28, about about 17.32, 17.32, aboutabout 18.93,18.93, about about 23.47,23.47, about 24.56, about 24.56, and and about 25.40 about 25.40 degrees degrees 20. 20. In In some some embodiments, FormV VofofCompound embodiments, Form Compound 1 is 1 is characterizedininthat characterized that it has it has eight eight or or more peaksininits more peaks its powder powderX-ray X-ray diffraction diffraction pattern pattern selected selected fromfrom thosethose at about at about

5.85, about 5.85, about 8.23, 8.23, about about11.02, 11.02,about about 11.15, 11.15, about about 12.69, 12.69, about about 13.34, 13.34, aboutabout 16.23,16.23, about about 16.28, 16.28,

23

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about 17.32, about 17.32,about about18.93, 18.93,about about 23.47, 23.47, about about 24.56, 24.56, and about and about 25.40 25.40 degrees degrees 20. In 20. some In some 2023206094 18 Jul 2023

embodiments, embodiments, Form Form V of V of Compound Compound 1 is characterized 1 is characterized inhas in that it thatnine it has or nine or more more peaks peaks in its in its powderX-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those at about at about 5.85,5.85, aboutabout 8.23, 8.23, about about 11.02, 11.02,

about 11.15, about 11.15,about about12.69, 12.69,about about 13.34, 13.34, about about 16.23, 16.23, aboutabout 16.28,16.28, about about 17.32,17.32, about about about 18.93, 18.93, about 23.47, about 23.47, about 24.56, 24.56,and andabout about25.40 25.40degrees degrees20.20.InIn some someembodiments, embodiments, Form Form V of Compound V of Compound 1 1

is characterized is in that characterized in that it it has has ten ten or or more peaksininits more peaks its powder powderX-ray X-ray diffraction diffraction pattern pattern selected selected

fromthose from thoseatatabout about5.85, 5.85,about about 8.23,about 8.23, about 11.02, 11.02, about about 11.15, 11.15, aboutabout 12.69,12.69, about about 13.34, 13.34, about about 16.23, about 16.23, about16.28, 16.28,about about17.32, 17.32,about about 18.93, 18.93, about about 23.47, 23.47, aboutabout 24.56, 24.56, and 25.40 and about about degrees 25.40 degrees 20. In 20. In some someembodiments, embodiments, Form Form V of Compound V of Compound 1 is characterized 1 is characterized in that it in hasthat it has eleven or eleven more or more peaksinin its peaks its powder X-ray powder X-ray diffraction diffraction pattern pattern selected selected from from those those at about at about 5.85,5.85, aboutabout 8.23, 8.23, about about

11.02, about 11.02, about11.15, 11.15,about about12.69, 12.69,about about 13.34, 13.34, about about 16.23, 16.23, aboutabout 16.28,16.28, about about 17.32, 17.32, about about 18.93, about 18.93, about23.47, 23.47,about about24.56, 24.56, andand about about 25.40 25.40 degrees degrees 20.someIn embodiments, 20. In some embodiments, Form V of Form V of Compound Compound 1 is 1characterized is characterized in that in that it has it has twelve twelve or more or more peakspeaks in itsinpowder its powder X-ray diffraction X-ray diffraction

pattern selected pattern selected from fromthose thoseatatabout about 5.85,about 5.85, about 8.23, 8.23, about about 11.02, 11.02, about about 11.15, 11.15, aboutabout 12.69,12.69,

about 13.34, about 13.34,about about16.23, 16.23,about about 16.28, 16.28, about about 17.32, 17.32, aboutabout 18.93,18.93, about about 23.47,23.47, about 24.56, about 24.56, and and about 25.40 about 25.40 degrees degrees 20. 20. In In some some embodiments, FormV VofofCompound embodiments, Form Compound 1 is 1 is characterizedininthat characterized that it has it has all allthirteen thirteenpeaks peaks in in its itspowder X-raydiffraction powder X-ray diffractionpattern patternselected selectedfrom from those those at at about about 5.85, 5.85,

about8.23, about 8.23, about about11.02, 11.02,about about 11.15, 11.15, about about 12.69, 12.69, about about 13.34, 13.34, aboutabout 16.23,16.23, about 16.28, about 16.28, about about 17.32, about 17.32, about18.93, 18.93,about about23.47, 23.47, about about 24.56, 24.56, and and about about 25.4025.40 degrees degrees 20. 20.

[0110] In some

[0110] In some embodiments, Form Form embodiments, V of Compound V of Compound 1 is characterized 1 is characterized in that in that it has oneone it has or or

morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those at about at about 8.0, about 8.0, about 11.0, 11.0, about12.7, about 12.7, about about13.3, 13.3,about about 16.3,about 16.3, about 17.9, 17.9, about about 20.3, 20.3, about about 22.6, 22.6, aboutabout 23.5,23.5, and about and about

24.6 degrees 24.6 degrees20. 20. In some

[0111] In some

[0111] embodiments, embodiments, the present the present invention invention provides provides a solvated crystalline form a solvatedcrystalline of form of

Compound Compound 1 referredtoto as 1 referred as Form VI. In Form VI. In some someembodiments, embodiments,the thepresent present invention invention provides provides FormVIVI Form of of Compound Compound 1, having 1, having a powder a powder X-ray diffraction X-ray diffraction pattern substantially pattern substantially similar tosimilar that to that depictedinin Figure depicted Figure11A. 11A.In some In some embodiments, embodiments, the present the present invention invention provides provides Form Form VI of VI of Compound Compound 1, having 1, having a powder a powder X-ray X-ray diffraction diffraction patternpattern substantially substantially similar similar to that to that depicted depicted in in Figure11B. Figure 11B.In In some some embodiments, embodiments, Form VIForm VI of Compound of Compound 1 is characterized 1 is characterized in athat in that it has it has a peaks in its peaks in its powder X-ray powder X-ray diffraction diffraction pattern pattern selected selected from from those those in Table in Table 7 below. 7 below.

Table 7. Table 7.Compound Compound 11 Form VI XRPD Form VI XRPDPeaks Peaks Position (°20) Position (°2) Height(cts) Height (cts) Relative Relative

Intensity(%) Intensity (%)

10.19 10.19 142.1 142.1 100 100

24

1004799942

[0112] In some

[0112] In some embodiments, embodiments, Form Form VI of VI of Compound Compound 1 is characterized 1 is characterized in that in that it hasa apeak it has peak 2023206094 18 Jul 2023

at about at 10.19degrees about 10.19 degrees2020in initsitspowder powder X-ray X-ray diffraction diffraction pattern. pattern.

[0113] In some

[0113] In some embodiments, embodiments, Form Form VI is VI is characterized characterized by X-ray by an an X-ray powder powder diffractogram diffractogram

comprisingthethefollowing comprising following peaks: peaks: 18.0, 18.0, 23.4, 23.4, and and 25.325.3 °20 ±°20 0.2 °20, 0.2 °20, as determined as determined on a on a diffractometerusing diffractometer usingCu-K Cu-Ko radiation radiation at a wavelength at a wavelength of 1.54of Å.1.54 A. The diffractogram The diffractogram comprises comprises additional peaks additional peaksatat10.5, 10.5, 14.2, 14.2,15.1, 15.1, and and18.8 18.8°2°20 ± 0.2 0.2 °2. °20. Compound Compound 1 Form VI1 is Form alsoVI is also characterizedbybyits characterized its X-ray X-raydiffraction diffractionpattern patternasassubstantially substantiallyshown shown in Figure in Figure 11A.11A. Compound Compound 1 1 FormVIVIis isalso Form alsocharacterized characterizedby by its its X-ray X-ray diffraction diffraction pattern pattern as substantially as substantially shown shown in Figure in Figure

11B. 11B.

In some

[0114] In some

[0114] embodiments, VI of VI Form Form embodiments, of Compound Compound 1 is characterized by a by 1 is characterized a differential differential

scanningcalorimetry scanning calorimetry(DSC) (DSC) curve curve that that comprises comprises an endotherms an endotherms at 193 at 131 °C, 131 °C, °C, and 193205 °C,°C.and 205 °C. FormVIVIof of Form Compound Compound 1 is characterized 1 is also also characterized by itsby DSCitscurve DSCascurve as substantially substantially shown in shown Figure in Figure 12. 12.

[0115] In some

[0115] In some embodiments, embodiments, Form Form VI of VI of Compound Compound 1 is characterized 1 is characterized by a by a thermogravimetric thermogravimetric analysis analysis (TGA) (TGA) curvecurve as substantially as substantially shown shown in 13. in Figure Figure 13. In some

[0116] In some

[0116] embodiments, embodiments, the present the present invention invention provides provides a polymorphic a polymorphic form form of of Compound Compound 1 referred 1 referred to Form to as as Form VII.someIn embodiments, VII. In some embodiments, theinvention the present present provides invention provides FormVII Form VIIofof Compound Compound 1, having 1, having a powder a powder X-ray diffraction X-ray diffraction pattern substantially pattern substantially similar similar to that to that depicted inin Figure depicted Figure14. 14.InInsome some embodiments, embodiments, Form Form VII VII of Compound of Compound 1 is characterized 1 is characterized in that in that it has it has one or more one or peaksininits more peaks its powder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from thosethose in Table in Table 8 8 below. below.

Table 8.8.Compound Table Compound 11 Form V1 XRPD Form VII Peaks XRPD Peaks

Position (°20) Position (°2) Height(cts) Height (cts) Relative Relative

Intensity(%) Intensity (%)

8.94 8.94 175.4 175.4 46 46

9.16 9.16 381.3 381.3 100 100

13.73 13.73 126.6 126.6 33.19 33.19

14.74 14.74 38.9 38.9 10.19 10.19

17.05 17.05 37.7 37.7 9.9 9.9

17.90 17.90 35.0 35.0 9.17 9.17

18.22 18.22 24.2 24.2 6.35 6.35

18.38 18.38 82.5 82.5 21.64 21.64

19.47 19.47 64.5 64.5 16.92 16.92

19.51 19.51 39.6 39.6 10.37 10.37

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22.37 22.37 43.3 43.3 11.36 11.36 2023206094 18 Jul 2023

23.85 23.85 35.8 35.8 9.39 9.39

23.94 23.94 24.2 24.2 6.36 6.36

25.53 25.53 37.8 37.8 9.9 9.9

25.96 25.96 137.4 137.4 36.03 36.03

27.17 27.17 38.5 38.5 10.1 10.1

27.76 27.76 38.5 38.5 10.1 10.1

[0117]

[0117] In In some embodiments, someembodiments, VII ofVII Form Form of Compound Compound 1 is characterized in that it in 1 is characterized that has has two or twoit or

morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those in Table in Table 8. In 8. In some some embodiments, embodiments, Form Form VIICompound VII of of Compound 1 is characterized 1 is characterized in has in that it thatthree it hasorthree more or more peaks in peaks its in its powderX-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those in Table in Table 8. In 8.some In embodiments, some embodiments, Form Form VII of VII ofCompound Compound1 is 1characterized is characterized in that in that it has it has fourfour or more or more peakspeaks in itsinpowder its powder X-ray X-ray diffraction pattern diffraction pattern selected selected from fromthose thoseininTable Table 8. 8. In In some some embodiments, embodiments, Form Form VII of VII of Compound Compound 1 is 1characterized is characterized in that in that it has it has five five or or more more peaks peaks in powder in its its powder X-ray X-ray diffraction diffraction

pattern selected pattern selected from fromthose thoseininTable Table 8. 8. In In some some embodiments, embodiments, Form Form VII VII of Compound of Compound 1 is 1 is characterizedininthat characterized that it it has has all all of of the the peaks in Table peaks in Table 88 in in its its X-ray diffraction pattern. X-ray diffraction pattern.

[0118] In some

[0118] In some embodiments, Form Form embodiments, VII VII of of Compound Compound 1 is characterized 1 is characterized in that in that it has oneoror it hasone morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those at about at about 8.94, 8.94, about about 17.90, and 17.90, and about about27.76 27.76degrees degrees 20;20; in addition in addition to having to having onemore one or or more peaks peaks selected selected from from about about 9.16, about 9.16, about 13.73, 13.73,about about14.74, 14.74,about about 17.05, 17.05, about about 18.22, 18.22, aboutabout 18.38, 18.38, about about 19.47, 19.47, about about 19.51, 19.51, about 22.37, about 22.37,about about23.85, 23.85,about about 23.94, 23.94, about about 25.53, 25.53, aboutabout 25.96, 25.96, and about and about 27.17 degrees 27.17 degrees 20. In 20. In someembodiments, some embodiments, Form Form VII ofVII of Compound Compound 1 is characterized 1 is characterized in that it in that has twoitor hasmore twopeaks or more peaks in its in itspowder X-raydiffraction powder X-ray diffractionpattern patternselected selectedfrom from those those at about at about 8.94, 8.94, about about 17.90, 17.90, and about and about

27.76 degrees 27.76 degrees20; 20;ininaddition additiontotohaving having oneone or more or more peakspeaks selected selected from 9.16, from about aboutabout 9.16, about 13.73, about 13.73, about14.74, 14.74,about about17.05, 17.05,about about 18.22, 18.22, about about 18.38, 18.38, aboutabout 19.47,19.47, about about 19.51, 19.51, about about 22.37, about 22.37, about23.85, 23.85,about about23.94, 23.94, about about 25.53, 25.53, about about 25.96, 25.96, and about and about 27.17 27.17 degreesdegrees 20. 20. In some In some embodiments, embodiments, Form Form VIICompound VII of of Compound 1 is characterized 1 is characterized in has in that it thatone it has one peaks or more or more peaks in its in its powderX-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those at about at about 8.94,8.94, aboutabout 17.90,17.90, and 27.76 and about about 27.76 degrees 20; degrees 20;inin addition additiontotohaving havinga peak a peak at at about about 25.96 25.96 degrees degrees 20.some 20. In In embodiments, some embodiments, Form Form VII of VII ofCompound Compound1 is 1characterized is characterized in that in that it has it has one one or more or more peakspeaks in itsin its powder powder X-ray X-ray diffraction pattern diffraction pattern selected selected from fromthose thoseatatabout about8.94, 8.94,andand about about 27.76 27.76 degrees degrees 20;addition 20; in in addition to to having aa peak having peak at at about about25.96 25.96degrees degrees20. 20.InInsome someembodiments, embodiments, Form VII of Form VII of Compound Compound 1 1isis

characterizedininthat characterized that it it has has all all three three peaks in its peaks in its powder X-raydiffraction powder X-ray diffractionpattern patternselected selected from from

those at those at about about8.94, 8.94, about about27.76, 27.76,andand about about 25.96 25.96 degrees degrees 20. 20.

26

1004799942

[0119] In some

[0119] In some embodiments, Form Form embodiments, VII VII of of Compound Compound 1 is characterized 1 is characterized in that in that it has oneoror it hasone 2023206094 18 Jul 2023

morepeaks more peaksin initsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those at about at about 9.2, about 9.2, about 13.7, 13.7, about 14.7, about 14.7, about about17.1, 17.1,about about18.4, 18.4,about about 19.5, 19.5, about about 22.4, 22.4, about about 23.9, 23.9, aboutabout 25.5,25.5, and about and about

26.0 degrees 26.0 degrees20. 20. In some

[0120] In some

[0120] embodiments, embodiments, the present the present invention invention provides provides a polymorphic a polymorphic form form of of Compound Compound 1 referred 1 referred to Form to as as Form VIII.VIII. In embodiments, In some some embodiments, theinvention the present present provides invention provides FormVIII Form VIIIof of Compound Compound 1, having 1, having a powder a powder X-ray diffraction X-ray diffraction pattern substantially pattern substantially similar tosimilar to that depicted that in Figure depicted in Figure15A. 15A.In Insome some embodiments, embodiments, the present the present invention invention providesprovides Form VIIIForm of VIII of Compound Compound 1, having 1, having a powder a powder X-ray X-ray diffraction diffraction patternpattern substantially substantially similar similar to that to that depicted depicted in in Figure15B. Figure 15B.In In some some embodiments, embodiments, Form Form VIII of VIII of Compound Compound 1 is characterized 1 is characterized in that in that it has one it has one or more or peaksin initsitspowder more peaks powder X-ray X-ray diffraction diffraction pattern pattern selected selected fromfrom thosethose in Table in Table 9 below. 9 below.

Table 9. Table 9.Compound Compound 11 Form VI XRPD Form VIII Peaks XRPD Peaks

Position (°20) Position (°2) Height(cts) Height (cts) Relative Relative

Intensity(%) Intensity (%)

5.50 5.50 18.8 18.8 24.4 24.4

8.95 8.95 28.2 28.2 36.6 36.6

10.31 10.31 42.4 42.4 54.9 54.9

12.90 12.90 16.6 16.6 21.5 21.5

15.82 15.82 77.2 77.2 100.0 100.0

17.84 17.84 27.3 27.3 35.4 35.4

18.77 18.77 36.3 36.3 47.0 47.0

20.40 20.40 54.0 54.0 70.0 70.0

22.23 22.23 25.3 25.3 32.8 32.8

22.71 22.71 43.4 43.4 56.2 56.2

25.83 25.83 32.6 32.6 42.2 42.2

27.73 27.73 22.5 22.5 29.2 29.2

In some

[0121] In some

[0121] Form Form embodiments, embodiments, VIII of of Compound VIIICompound 1 is characterized 1 is characterized in that it it in that hashastwo two or more or peaksininits more peaks itspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected fromfrom thosethose in Table in Table 9. In 9. someIn some embodiments, embodiments, Form Form VIII VIII of Compound of Compound 1 is characterized 1 is characterized in has in that it thatthree it hasorthree more or more peaks in peaks its in its powderX-ray powder X-ray diffraction diffraction pattern pattern selected selected fromfrom those those in Table in Table 9. In 9.some In embodiments, some embodiments, Form Form VIII of VIII of Compound Compound 1 is 1characterized is characterized in that in that it has it has fourfour or more or more peakspeaks in itsinpowder its powder X-ray X-ray diffraction pattern diffraction pattern selected selected from fromthose thoseininTable Table 9. 9. In In some some embodiments, embodiments, Form Form VIII of VIII of Compound Compound 1 is 1characterized is characterized in that in that it has it has five five or or more more peaks peaks in powder in its its powder X-ray X-ray diffraction diffraction

27

1004799942

pattern selected pattern selected from fromthose thoseininTable Table 9. 9. In In some some embodiments, embodiments, Form Form VIII VIII of Compound of Compound 1 is 1 is 2023206094 18 Jul 2023

characterizedininthat characterized that it it has has all all of of the the peaks in Table peaks in Table 99 in in its its X-ray diffraction pattern. X-ray diffraction pattern. In some

[0122] In some

[0122] Form Form embodiments, embodiments, VIII of of Compound VIIICompound 1 is characterized 1 is characterized in that in that it it hashasone one or more or peaksininits more peaks itspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from thosethose at about at about 5.50, 5.50, about about 10.31, about 10.31, about18.77, 18.77,about about22.23, 22.23,andand about about 25.83 25.83 degrees degrees 20.someInembodiments, 20. In some embodiments, Form VIII Form VIII of Compound of Compound 1 is1 characterized is characterized in that in that it has it has twotwo or more or more peakspeaks in itsinpowder its powder X-ray diffraction X-ray diffraction

pattern selected pattern selected from fromthose thoseatatabout about5.50, 5.50,about about 10.31, 10.31, about about 18.77, 18.77, aboutabout 22.23, 22.23, and and about about 25.83 degrees 25.83 degrees20. 20.In In some some embodiments, embodiments, Form Form VIII of VIII of Compound Compound 1 is characterized 1 is characterized in that it in that it has three has three or or more morepeaks peaksin in itsitspowder powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from those those at about at about 5.50, 5.50, about 10.31, about 10.31,about about18.77, 18.77,about about 22.23, 22.23, and and about about 25.8325.83 degrees degrees 20. In20. someInembodiments, some embodiments, FormVIII Form VIIIofof Compound Compound 1 is characterized 1 is characterized init in that that hasit four has four or more or more peaks peaks in its in its powder powder X-ray X-ray diffraction pattern diffraction pattern selected selected from fromthose thoseatatabout about5.50, 5.50,about about 10.31, 10.31, about about 18.77, 18.77, about about 22.23, 22.23, and and about 25.83 about 25.83 degrees degrees 20. 20. In In some some embodiments, FormVIII embodiments, Form VIIIofofCompound Compound 1 ischaracterized 1 is characterized in in that it that it has has all allfive fivepeaks peaks in in its itspowder powder X-ray diffractionpattern X-ray diffraction patternselected selectedfrom from those those at at about about 5.50, 5.50,

about10.31, about 10.31,about about18.77, 18.77,about about 22.23, 22.23, and and about about 25.8325.83 degrees degrees 20. 20.

[0123] In some

[0123] In some embodiments, Form Form embodiments, VIII of of Compound VIIICompound 1 is characterized 1 is characterized in that in that it has one it hasone or more or peaksin initsitspowder more peaks powder X-ray X-ray diffraction diffraction pattern pattern selected selected from from thosethose at about at about 5.5, about 5.5, about

10.3, about 10.3, 15.8, about about 15.8, about18.8, 18.8,about about20.4, 20.4,about about 22.7, 22.7, andand about about 25.825.8 degrees degrees 20. 20.

[0124] In some

[0124] In some embodiments, embodiments, Form Form VIIIcharacterized VIII is is characterized by by an X-ray an X-ray powder powder diffractogram diffractogram

comprisingthethefollowing comprising following peaks: peaks: 16.0, 16.0, 20.5, 20.5, and and 22.8 22.8 °20 ±°20 0.2 as 0.2 °20, °20,determined as determined on a on a diffractometerusing diffractometer usingCu-K Cu-Ko radiation radiation at a wavelength at a wavelength of 1.54of Å. 1.54 A. The diffractogram The diffractogram comprises comprises additional peaks additional peaksatat9.1, 9.1, 10.5, 10.5, 18.8, 18.8, and and25.8 25.8°20°20± 0.20.2°20. °20.Compound Compound 1 Form 1VIII Formis VIII also is also characterizedbybyits characterized its X-ray X-raydiffraction diffractionpattern patternasassubstantially substantiallyshown shown in Figure in Figure 15A. 15A. Compound Compound 1 1 FormVIII Form VIIIis isalso alsocharacterized characterized by by itsits X-ray X-ray diffraction diffraction pattern pattern as substantially as substantially shown shown in Figure in Figure

15B. 15B.

In some

[0125] In some

[0125] embodiments, Form Form embodiments, VIII of of Compound VIIICompound 1 is characterized by a by 1 is characterized a differential differential

scanningcalorimetry scanning calorimetry (DSC) (DSC) curve curve that that comprises comprises an endotherm an endotherm at Form at 205 °C. 205 °C. VIII Form of VIII of Compound Compound 1 is1also is also characterized characterized by DSC by its its DSC curve curve as substantially as substantially shown shown in in16. Figure Figure 16.

[0126] In some

[0126] In some embodiments, embodiments, Form Form VIIICompound VIII of of Compound 1 is characterized 1 is characterized by a by a thermogravimetric thermogravimetric analysis analysis (TGA) (TGA) curve curve as substantially as substantially shown shown in in 17. Figure Figure 17.

[0127] SomeSome

[0127] hereinherein embodiments embodiments provide for afor provide a crystalline crystalline form of of form a sodium a sodium salt co saltororco- crystal ofofCompound crystal 1, which Compound 1, is referred which is referredtoto as as Compound Compound 11 Sodium FormI. Sodium Form I. In In some some

embodiments,Compound embodiments, Compound 1 Sodium 1 Sodium FormForm I is Icharacterized is characterizedbybyananX-ray X-raypowder powder diffractogram diffractogram

comprisingthethefollowing comprising following peaks: peaks: 7.5,7.5, 8.2,8.2, 20.4, 20.4, andand 20.920.9 °2 ±°20 0.2 as 0.2 °20, °20, as determined determined on a on a diffractometerusing diffractometer usingCu-K Cu-Ko radiation radiation at a wavelength at a wavelength of 1.54of Å. 1.54 A. The diffractogram The diffractogram comprises comprises

28

1004799942

additional peaks additional peaksatat14.8, 14.8, 17.5, 17.5,24.0, 24.0,and and27.7 27.7°2°20 ± 0.2 0.2 °2. °20. Compound Compound 1 Sodium 1Form Sodium Form I is also I is also 2023206094 18 Jul 2023

characterizedbybyits characterized its full full X-ray X-raydiffraction diffractionpattern patternasassubstantially substantiallyshown shownin in Figure Figure 19. 19. In some

[0128] In some

[0128] embodiments, embodiments, Compound Compound 1 Sodium 1 Sodium Form Form I is I is characterized characterized by a differential by a differential

scanningcalorimetry scanning calorimetry (DSC) (DSC) curve curve that that comprises comprises an endotherm an endotherm at about at 37about °C and37 an°C and an endotherm at endotherm at about about 283 °C. Compound 283 °C. 1 Sodium Compound 1 Sodium Form Form I alsoisischaracterized I also characterized by by its itsDSC DSC curve curve

as substantially as shownininFigure substantially shown Figure 20.20.

[0129] In some

[0129] In some embodiments, embodiments, Compound Compound 1 Sodium 1 Sodium Form Form I is I is characterized characterized by a by a thermogravimetric thermogravimetric analysis analysis (TGA) (TGA) curvecurve as substantially as substantially shown shown in in 21. Figure Figure 21.

[0130] SomeSome

[0130] hereinherein embodiments embodiments provide for afor provide a crystalline crystalline form of of form a sodium a sodium salt co saltororco- crystal of crystal of Compound 1, which Compound 1, which is referred is referred to Compound to as as Compound 1 Sodium1 Form Sodium Form II. In someII. In some embodiments, Compound embodiments, Compound 1 Sodium 1 Sodium FormForm II characterized II is is characterizedbybyananX-ray X-raypowder powder diffractogram diffractogram

comprisingthethefollowing comprising following peaks: peaks: 4.8,4.8, 6.7, 6.7, 15.6, 15.6, andand 24.224.2 °20 °20 0.2 °20, ± 0.2 °20, as determined as determined on a on a diffractometerusing diffractometer usingCu-K Cu-Ko radiation radiation at a wavelength at a wavelength of 1.54of Å. 1.54 A. The diffractogram The diffractogram comprises comprises additional peaks additional peaksatat17.9, 17.9, 29.2, 29.2,32.5, 32.5, and and38.0 38.0°2°20 ± 0.2 0.2 °2. °20. Compound Compound 1 Sodium 1Form Sodium II is Form also II is also characterizedbybyits characterized its full full X-ray X-raydiffraction diffractionpattern patternasassubstantially substantiallyshown shown in Figure in Figure 22. 22.

[0131] In some

[0131] In some embodiments, embodiments, Compound Compound 1 Sodium 1 Sodium Form II Form II is characterized is characterized by a by a differential scanning differential calorimetry(DSC) scanning calorimetry (DSC) curve curve that that comprises comprises an endotherm an endotherm at about at 19about °C, an19 °C, an endothermat endotherm at about about 78 78 °C, °C, and and an an endotherm at about endotherm at about 136 136 °C. °C.Compound Compound 11 Sodium SodiumForm Form IIIIalso also is characterized is byits characterized by its DSC DSCcurve curve as as substantially substantially shown shown in Figure in Figure 23. 23.

[0132] In some

[0132] In some embodiments, embodiments, Compound Compound 1 Sodium 1 Sodium Form II Form II is characterized is characterized by a by a thermogravimetric thermogravimetric analysis analysis (TGA) (TGA) curvecurve as substantially as substantially shown shown in in 24. Figure Figure 24.

[0133] SomeSome

[0133] embodiments hereinherein embodiments provide for afor provide a crystalline crystalline form of of form a calciumsalt a calcium or co- salt or co crystal of crystal of Compound 1, which Compound 1, which is referred is referred to Compound to as as Compound 1 Calcium 1 Calcium Form I. InForm some I. In some embodiments,Compound embodiments, Compound 1 Calcium 1 Calcium FormForm I isI characterized is characterizedbybyananX-ray X-raypowder powder diffractogram diffractogram

comprisingthethefollowing comprising following peaks: peaks: 10.1, 10.1, 14.3, 14.3, and and 20.4 20.4 °2 ± °20 0.2as°20, 0.2 °20, as determined determined on a on a diffractometerusing diffractometer usingCu-K Cu-Ko radiation radiation at a wavelength at a wavelength of 1.54of Å. 1.54 A. The diffractogram The diffractogram comprises comprises additional peaks additional peaksatat3.6, 3.6, 7.8, 7.8, 21.6, 21.6, 27.3, 27.3, 28.9 28.9 °2°20± 0.20.2 °20. °20. Compound Compound 1 Calcium 1 Calcium Form Form I is also I is also characterizedbybyits characterized its full full X-ray X-raydiffraction diffractionpattern patternasassubstantially substantiallyshown shown in Figure in Figure 25. 25. In some

[0134] In some

[0134] embodiments, embodiments, Compound Compound 1 Calcium Form I Form 1 Calcium I is characterized is characterized by a differential by a differential

scanningcalorimetry scanning calorimetry (DSC) (DSC) curve curve that that comprises comprises an endotherm an endotherm at about at 17about °C, an17 °C, an endotherm endotherm at at about 72 about 72 °C, °C, an an endotherm endotherm at at about about 180 180 °C, °C,and andan anendotherm endotherm at atabout about202 202°C. °C.Compound Compound 11

CalciumForm Calcium Form I also I also is characterized is characterized by its by its DSCDSC curvecurve as substantially as substantially shown shown in 26. in Figure Figure 26.

[0135] In some

[0135] In some embodiments, embodiments, Compound Compound 1 Calcium 1 Calcium Form I Form I is characterized is characterized by a by a thermogravimetric thermogravimetric analysis analysis (TGA) (TGA) curve curve as substantially as substantially shown shown in in 27. Figure Figure 27.

29

1004799942

[0136] SomeSome

[0136] embodiments hereinherein embodiments provide for afor provide a crystalline crystalline form of of form a magnesium ororco- saltsalt a magnesium co 2023206094 18 Jul 2023

crystal ofofCompound crystal 1, which Compound 1, is referred which is referredto to as as Compound Compound 11 Magnesium FormI.I. In Magnesium Form In some some embodiments, Compound embodiments, Compound 1 Magnesium 1 Magnesium Form Form I is characterized I is characterized by by an an X-ray X-ray powder powder

diffractogramcomprising diffractogram comprising the the following following peaks: peaks: 8.2, 16.9, 8.2, 16.9, 19.1, 19.1, and°221.2 and 21.2 °20°2, 0.2 ± 0.2 as °20, as determinedonon determined a diffractometer a diffractometer using using Cu-KCu-Kc radiation radiation at a wavelength at a wavelength ofThe of 1.54 Å. 1.54 A. The diffractogramcomprises diffractogram comprises additional additional peaks peaks at 15.8, at 15.8, 24.1, 24.1, 26.1, 26.1, and 27.1 and 27.1 °20 ± °20 0.2Compound 0.2 °2. °20. Compound 1 Magnesium 1 Form Magnesium Form I is Ialso is also characterized characterized byfull by its its full X-ray X-ray diffraction diffraction pattern pattern as substantially as substantially

shownininFigure shown Figure28.28.

[0137] In some

[0137] In some embodiments, embodiments, Compound Compound 1 Magnesium 1 Magnesium Form Form I is I is characterized characterized by a by a differential scanning differential calorimetry(DSC) scanning calorimetry (DSC) curve curve that that comprises comprises an endotherm an endotherm at aboutat53about °C. 53 °C. Compound Compound 1 Magnesium 1 Magnesium FormForm I also I also is is characterizedbybyits characterized its DSC curveasas substantially DSC curve substantially shown shown

in Figure in 29. Figure 29.

[0138] In some

[0138] In some embodiments, embodiments, Compound Compound 1 Magnesium 1 Magnesium Form Form I is I is characterized characterized by a by a thermogravimetric thermogravimetric analysis analysis (TGA) (TGA) curvecurve as substantially as substantially shown shown in in 30. Figure Figure 30.

[0139] SomeSome

[0139] embodiments hereinherein embodiments provide for afor provide a crystalline crystalline form form of of a diethanolaminesalt a diethanolamine or salt or co-crystal of co-crystal of Compound Compound 1, which 1, which is referred is referred to astoCompound as Compound 1 Diethanolamine 1 Diethanolamine Form I. In Form some I. In some embodiments, Compound embodiments, Compound 1 Diethanolamine 1 Diethanolamine FormForm I isI characterized is characterizedbybyananX-ray X-raypowder powder diffractogramcomprising diffractogram comprising the the following following peaks: peaks: 5.1, 5.1, 8.0, 8.0, 17.0,17.0, 25.1 25.1 °20 ±°20 0.2 as 0.2 °20, °20,determined as determined on aa diffractometer on diffractometerusing usingCu-K Cu-Ko radiation radiation at a wavelength at a wavelength of 1.54of Å.1.54 A. The diffractogram The diffractogram

comprisesadditional comprises additionalpeaks peaks at at 13.4, 13.4, 16.4, 16.4, 20.4, 20.4, andand 22.6 22.6 °2 ±°20 0.2 Compound 0.2 °20. °20. Compound 1 1 Diethanolamine Diethanolamine Form Form I is Ialso is also characterized characterized byfull by its its full X-ray X-ray diffraction diffraction pattern pattern as substantially as substantially

shownininFigure shown Figure31.31.

[0140] In some

[0140] In some embodiments, embodiments, Compound Compound 1 Diethanolamine 1 Diethanolamine Form I Form I is characterized is characterized by a by a differential scanning differential calorimetry(DSC) scanning calorimetry (DSC) curve curve that that comprises comprises an endotherm an endotherm at aboutat118 about °C. 118 °C. Compound Compound 1 Diethanolamine 1 Diethanolamine Form I Form I also also is is characterized characterized by curve by its DSC its DSC curve as substantially as substantially

shownininFigure shown Figure32.32.

[0141] In some

[0141] In some embodiments, embodiments, Compound Compound 1 Diethanolamine 1 Diethanolamine Form I Form I is characterized is characterized by a by a thermogravimetric thermogravimetric analysis analysis (TGA) (TGA) curvecurve as substantially as substantially shown shown in in 33. Figure Figure 33. Some embodiments

[0142] Some embodiments

[0142] herein herein provide provide for for a crystalline a crystalline form of a salt form of a piperazine piperazine or co- salt or co crystal of crystal of Compound 1, which Compound 1, which is referred is referred to Compound to as as Compound 1 Piperazine 1 Piperazine Form Form I. In someI. In some embodiments, Compound embodiments, Compound 1 Piperazine 1 Piperazine Form Form I ischaracterized I is characterized by by an an X-ray X-ray powder powder diffractogramcomprising diffractogram comprising the the following following peaks: peaks: 5.6, 5.6, 8.0, 8.0, 10.5,10.5, and °20 and 15.9 15.9± °20 0.2as°20, 0.2 °2, as determinedonon determined a diffractometer a diffractometer using using Cu-KCu-Kc radiation radiation at a wavelength at a wavelength ofThe of 1.54 Å. 1.54 A. The diffractogramcomprises diffractogram comprises additional additional peaks peaks at 13.3, at 13.3, 17.9,17.9, 22.1, 22.1, and 24.3 and 24.3 °20 ± °20 0.2Compound 0.2 °2. °20. Compound

30

1004799942

1 Piperazine 1 Form Piperazine Form I isalso I is alsocharacterized characterizedby by itsits fullX-ray full X-ray diffractionpattern diffraction pattern as as substantially substantially 2023206094 18 Jul 2023

shownininFigure shown Figure 34.34.

[0143] In some

[0143] In some embodiments, embodiments, Compound Compound 1 Piperazine 1 Piperazine Form IForm I is characterized is characterized by a by a differential scanning differential calorimetry(DSC) scanning calorimetry (DSC) curve curve that that comprises comprises an endotherm an endotherm at aboutat27about 27 °C and °C and an endotherm an endotherm at at about about 139139 °C. °C. Compound Compound 1 Piperazine 1 Piperazine Form Form I also is Icharacterized also is characterized by its DSCby its DSC curve asas substantially curve substantially shown shownin in Figure Figure 35.35.

[0144] In some

[0144] In some embodiments, embodiments, Compound Compound 1 Piperazine 1 Piperazine Form IForm I is characterized is characterized by a by a thermogravimetric thermogravimetric analysis analysis (TGA) (TGA) curvecurve as substantially as substantially shown shown in in 36. Figure Figure 36.

3. Compounds 3. Compounds andand definitions definitions

Compounds

[0145] Compounds

[0145] of this of this invention invention include include those those described described generallyabove, generally arefurther andare above,and further illustrated by illustrated by the the classes, classes, subclasses, andspecies subclasses, and speciesdisclosed disclosedherein. herein.As As usedused herein, herein, the the following following

definitions shall definitions shall apply unlessotherwise apply unless otherwiseindicated. indicated.ForFor purposes purposes of this of this invention, invention, the chemical the chemical

elementsare elements areidentified identifiedininaccordance accordance with with the the Periodic Periodic Table Table of Elements, of the the Elements, CAS version, CAS version,

Handbook Handbook of of Chemistry Chemistry and Physics, and Physics, Ed. Additionally, 75th Ed. thAdditionally, 75 general general principles principles of of organic organic chemistryare chemistry aredescribed describedin in "Organic "Organic Chemistry" Chemistry" ThomasThomas Sorrell,Sorrell, University University Science Science Books, Books, Sausalito: 1999, Sausalito: 1999, and and "March's "March's Advanced OrganicChemistry", Advanced Organic Chemistry",5 5Ed., th Ed.,Ed.: Ed.:Smith, Smith,M.B. M.B.and and March,J., March, J., John JohnWiley Wiley & Sons, & Sons, New New York: York: 2001, 2001, the thecontents entire entire contents of which of arewhich herebyare hereby incorporatedbybyreference. incorporated reference.

[0146] The term

[0146] The "aliphatic" term "aliphatic" or "aliphatic or "aliphatic group",group", as used as used means herein, herein,a straight-chain means a straight-chain (i.e., (i.e., unbranched)or or unbranched) branched, branched, substituted substituted or unsubstituted or unsubstituted hydrocarbon hydrocarbon chainis that chain that is completely completely

saturated or saturated or that that contains oneorormore contains one more units units of of unsaturation, unsaturation, or or a monocyclic a monocyclic hydrocarbon hydrocarbon or or bicyclic hydrocarbon bicyclic hydrocarbon thatis iscompletely that completely saturated saturated or that or that contains contains one one or more or more units units of of unsaturation, but unsaturation, butwhich whichis isnot notaromatic aromatic (also (also referred referred to to herein herein as "carbocycle," as "carbocycle," "cycloaliphatic" "cycloaliphatic"

or "cycloalkyl"), or that has "cycloalkyl"), that has aa single single point pointofofattachment attachmentto tothetherest restofofthe themolecule. molecule.Unless Unless otherwisespecified, otherwise specified,aliphatic aliphaticgroups groupscontain contain 1-61-6 aliphatic aliphatic carbon carbon atoms. atoms. In embodiments, In some some embodiments, aliphatic groups aliphatic contain1-51-5aliphatic groups contain aliphaticcarbon carbon atoms. atoms. In other In other embodiments, embodiments, aliphatic aliphatic groups groups contain 1-4 contain 1-4aliphatic aliphaticcarbon carbon atoms. atoms. In still In still other other embodiments, embodiments, aliphatic aliphatic groups groups containcontain 1-3 1-3 aliphatic carbon aliphatic carbonatoms, atoms,andand in in yetother yet other embodiments, embodiments, aliphatic aliphatic groups groups contain contain 1-2 aliphatic 1-2 aliphatic

carbonatoms. carbon atoms.In In some some embodiments, embodiments, "cycloaliphatic" "cycloaliphatic" (or "carbocycle" (or "carbocycle" or "cycloalkyl") or "cycloalkyl") refers refers monocyclic C3-C hydrocarbon that isthat to aa monocyclicC3-C6hydrocarbon to is completely completely saturated saturated or that or that contains contains one one or more or more units of units of unsaturation, but which unsaturation, but whichisisnot notaromatic, aromatic,that thathashasa single a singlepoint point of of attachment attachment to the to the restrest

of the of molecule.Suitable the molecule. Suitable aliphaticgroups aliphatic groups include, include, but but are are not not limited limited to, to, linear linear or branched, or branched,

substituted or substituted or unsubstituted unsubstitutedalkyl, alkyl,alkenyl, alkenyl,alkynyl alkynylgroups groups andand hybrids hybrids thereof thereof such such as as (cycloalkyl)alkyl, (cycloalkenyl)alkyl (cycloalkyl)alkyl, (cycloalkenyl)alkylor or (cycloalkyl)alkenyl. (cycloalkyl)alkenyl.

31

1004799942

[0147] The term

[0147] The"lower term "lower alkyl" to alkyl" refers refers to straight a C1-4 aC1-4 straight or branched or branched alkylExemplary alkyl group. group. Exemplary 2023206094 18 Jul 2023

loweralkyl lower alkylgroups groupsarearemethyl, methyl, ethyl, ethyl, propyl, propyl, isopropyl, isopropyl, butyl, butyl, isobutyl, isobutyl, andand tert-butyl. tert-butyl.

[0148] term "lower The "lower

[0148] The term haloalkyl" haloalkyl" refers refers to a C1-4 aC1-4straight tostraight or branched or branched alkyl alkyl group group that is that is substituted with substituted with one oneorormore more halogen halogen atoms. atoms.

[0149] The The

[0149] termterm "heteroatom" "heteroatom" means means onemore one or or more of oxygen, of oxygen, sulfur, sulfur, nitrogen,phosphorus, nitrogen, phosphorus, or silicon or silicon (including, anyoxidized (including, any oxidizedform form of of nitrogen, nitrogen, sulfur, sulfur, phosphorus, phosphorus, or silicon; or silicon; the the quaternizedform quaternized formof of any any basic basic nitrogen nitrogen or; or; a substitutable a substitutable nitrogen nitrogen of aof a heterocyclic heterocyclic ring,ring, for for exampleN N example (as(as in in 3,4-dihydro-2H-pyrrolyl), 3,4-dihydro-2H-pyrroly]), NHin (as NH (as in pyrrolidinyl) pyrrolidinyl) or NR or NR (as (as in N-substituted in N-substituted

pyrrolidinyl)). pyrrolidinyl)).

[0150] The term

[0150] The "unsaturated," term "unsaturated," as used as used means herein, herein,that means that has a moiety a moiety one or has moreone or of units more units of unsaturation. unsaturation.

[0151] As used

[0151] As herein, used herein, the"bivalent the term term "bivalent C1-8 (orCi-8 C-6)(orC1-6) saturated saturated or unsaturated, or unsaturated, straight straight or or branched,hydrocarbon branched, hydrocarbon chain", chain", refers refers to bivalent to bivalent alkylene, alkylene, alkenylene, alkenylene, and alkynylene and alkynylene chains chains that are that are straight straight or or branched as defined branched as definedherein. herein.

[0152] The term

[0152] The "alkylene" term "alkylene" refers refers to to a bivalent a bivalent alkyl An alkyl group. group. An "alkylene "alkylene chain" is achain" is a polymethylene polymethylene group, group, i.e.,-(CH)n-, i.e., -(CH2)n-, wherein wherein n is anpositive is a positive integer, integer, preferably preferably from 1from to 6,1 from to 6, from 1 to 1 to 4, 4, from from 1 to 3, 1 to 3, from from 1 to 2, 1 to 2, or or from from 22 to to 3. 3. AA substituted substitutedalkylene alkylenechain chain is is a a polymethylene polymethylene

groupininwhich group whichoneone or or more more methylene methylene hydrogen hydrogen atoms atoms are are replaced replaced with a substituent. with a substituent. Suitable Suitable substituents include substituents includethose thosedescribed described below below for for a substituted a substituted aliphatic aliphatic group. group.

[0153] The term

[0153] The "alkenylene" term "alkenylene" refers refers to to a bivalent a bivalent alkenyl alkenyl group. A group. A substituted substituted alkenylene alkenylene chain is chain is aa polymethylene group polymethylene group containing containing at least at least one one double double bond bond in in one which which one or more or more hydrogenatoms hydrogen atoms areare replaced replaced withwith a substituent. a substituent. Suitable Suitable substituents substituents include include those those described described

belowfor below fora asubstituted substitutedaliphatic aliphaticgroup. group.

[0154] "Alkoxy"

[0154] "Alkoxy" refers refers to the to the group group "alkyl-O-".Examples "alkyl-O-". Examplesof of alkoxygroups alkoxy groupsinclude include methoxy,ethoxy, methoxy, ethoxy, n-propoxy, n-propoxy, iso-propoxy, iso-propoxy, n-butoxy, n-butoxy, tert-butoxy, tert-butoxy, sec-butoxy, sec-butoxy, n-pentoxy, n-pentoxy, n- n hexoxy, and hexoxy, and 1,2-dimethylbutoxy. 1,2-dimethylbutoxy.

[0155] The The

[0155] termterm "halogen" "halogen" means means F, Cl, F, Cl, Br, Br, or or I. I.

[0156] The term

[0156] The "ring" term "ring" means ameans a cycloalkyl cycloalkyl group or heterocyclic group or heterocyclic ring as ring as defined defined herein. herein.

[0157] The term

[0157] The "aryl" term "aryl" usedoralone used alone or as as part of part of a moiety a larger larger as moiety as in "aralkyl," in "aralkyl," "aralkoxy," "aralkoxy,"

or "aryloxyalkyl," or referstotomonocyclic "aryloxyalkyl," refers monocyclicor or bicyclic bicyclic ring ring systems systems having having a total a total of five of five to fourteen to fourteen

ring members, ring wherein members, wherein at least at least oneone ringring in the in the system system is aromatic is aromatic and wherein and wherein each each ring in ring the in the systemcontains system contains3 3toto7 7ring ringmembers. members. The "aryl" The term term "aryl" may be may used be used interchangeably interchangeably with the with the term"aryl term "aryl ring." ring."

[0158] The term

[0158] The "aryl" term "aryl" usedoralone used alone or as as part of part of a moiety a larger larger as moiety as in "aralkyl," in "aralkyl," "aralkoxy," "aralkoxy,"

or "aryloxyalkyl," or referstotomonocyclic "aryloxyalkyl," refers monocyclicandand bicyclic bicyclic ringring systems systems having having a total a total of to of five five10to 10

32

1004799942

ring members, ring members,wherein wherein at least at least oneone ringring in the in the system system is aromatic is aromatic and wherein and wherein eachin ring each ring the in the 2023206094 18 Jul 2023

systemcontains system containsthree threetotoseven seven ring ring members. members. The"aryl" The term term "aryl" may be may be used interchangeably used interchangeably

with the with the term term"aryl "arylring". ring".InIncertain certainembodiments embodiments ofpresent of the the present invention, invention, "aryl""aryl" refersrefers to an to an aromaticring aromatic ringsystem system which which includes, includes, but but not not limited limited to, phenyl, to, phenyl, biphenyl, biphenyl, naphthyl, naphthyl, anthracyl anthracyl

and the and the like, like, which may which may bear bear oneone or more or more substituents. substituents. Also included Also included within within theofscope the scope the of the term "aryl," term "aryl," asas it it isis used used herein, herein, is is aa group in which group in anaromatic which an aromatic ring ring is is fused fused to to one one or or more more

non-aromatic non-aromatic rings, rings, such such as as indanyl, indanyl, phthalimidyl, phthalimidyl, naphthimidyl, naphthimidyl, phenanthridinyl, phenanthridinyl, or or tetrahydronaphthyl,andand tetrahydronaphthyl, thethe like. like.

[0159] The term

[0159] term "aralkyl" The "aralkyl" refers refers to to aryl-alkylene, aryl-alkylene, aryl and aryl wherein wherein and alkylene alkylene are as are as defined defined herein. herein.

[0160] term "aralkoxy" The "aralkoxy"

[0160] The term refers refers to to aryl-alkoxy, aryl-alkoxy, wherein wherein aryl and alkoxy are alkoxy aryl and are as defined as defined herein. herein.

[0161]

[0161] The term"aryloxyalkyl" The term "aryloxyalkyl" refers refers to aryl-O-alkylene, to aryl-O-alkylene, wherein wherein arylalkylene aryl and are as are as and alkylene defined herein. defined herein.

[0162] The terms

[0162] The terms "heteroaryl" "heteroaryl" and "heteroar-," and "heteroar-," used used alone alone or as part or ofas a part ofmoiety, larger a largere.g., moiety, e.g., "heteroaralkyl," oror"heteroaralkoxy," "heteroaralkyl," "heteroaralkoxy,"refer refer to to groups groups having having 5 to 510toring 10 ring atoms, atoms, preferably preferably 5, 6, 5, 6, or 99 ring or atoms; having ring atoms; having6,6,10, 10,oror1414electrons x electrons shared shared in a in a cyclic cyclic array; array; and and having, having, in addition in addition

to carbon to carbonatoms, atoms,from from oneone to to five five heteroatoms. heteroatoms. Heteroaryl Heteroaryl groupsgroups include, include, without without limitation, limitation,

thienyl, furanyl, thienyl, furanyl, pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl,triazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, tetrazolyl, oxazolyl, oxazolyl, isoxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, oxadiazolyl, thiazolyl, isothiazolyl, isothiazolyl, thiadiazolyl, thiadiazolyl, pyridyl, pyridyl, pyridazinyl, pyridazinyl,pyrimidinyl, pyrimidinyl,pyrazinyl, pyrazinyl, indolizinyl, purinyl, indolizinyl, purinyl, naphthyridinyl, andpteridinyl. naphthyridinyl, and pteridinyl.The The terms terms "heteroaryl" "heteroaryl" and "heteroar-", and "heteroar-", as as used herein, used herein, also also include includegroups groupsin inwhich which a heteroaromatic a heteroaromatic ring ring is fused is fused to or to one onemore or aryl, more aryl, cycloaliphatic, or cycloaliphatic, or heterocyclyl heterocyclylrings, rings,where wherethethe radical radical or or point point of of attachment attachment is the is on on the heteroaromaticring. heteroaromatic ring.Nonlimiting Nonlimiting examples examples include include indolyl, indolyl, isoindolyl, isoindolyl, benzothienyl, benzothienyl,

benzofuranyl,dibenzofuranyl, benzofuranyl, dibenzofuranyl, indazolyl, indazolyl, benzimidazolyl, benzimidazolyl, benzthiazolyl, benzthiazolyl, quinolyl, quinolyl, isoquinolyl, isoquinolyl,

cinnolinyl, phthalazinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinazolinyl,quinoxalinyl, quinoxalinyl, 4H-quinolizinyl, 4H-quinolizinyl, carbazolyl, carbazolyl, acridinyl, acridinyl,

phenazinyl,phenothiazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroisoquinolinyl, and and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A A pyrido[2,3-b]-1,4-oxazin-3(4H)-one. heteroarylgroup heteroaryl groupmay maybebe mono- mono- or or bicyclic.The bicyclic. The term term

"heteroaryl" may "heteroaryl" maybe be used used interchangeably interchangeably with with the terms the terms "heteroaryl "heteroaryl ring," ring," "heteroaryl "heteroaryl group," group,"

or "heteroaromatic," or any "heteroaromatic," any of of which which terms terms include include ringsrings that that are optionally are optionally substituted. substituted. The The term term "heteroaralkyl"refers "heteroaralkyl" referstotoananalkyl alkylgroup groupsubstituted substituted by by a heteroaryl, a heteroaryl, wherein wherein the alkyl the alkyl and and heteroaryl portions heteroaryl portionsindependently independentlyareare optionally optionally substituted. substituted.

used herein, As herein,

[0163] As used

[0163] the terms terms "heterocycle," the "heterocycle," "heterocyclyl," "heterocyclyl," "heterocyclic "heterocyclic radical," radical," and and "heterocyclic ring" "heterocyclic ring"are areused usedinterchangeably interchangeably and and referrefer to ato a stable stable 5-7-membered 5- to to 7-membered monocyclic monocyclic

or 77 to or to 10-membered bicyclic 10-membered bicyclic heterocyclic heterocyclic moiety moiety that that is is either either saturated saturated or partially or partially

33

1004799942

unsaturated, and unsaturated, andhaving, having,ininaddition addition to to carbon carbon atoms, atoms, one one or more, or more, preferably preferably one toone to four, four, 2023206094 18 Jul 2023

heteroatoms,asasdefined heteroatoms, definedabove. above. When When used used in in reference reference to aatom to a ring ring of atom of a heterocycle, a heterocycle, the termthe term "nitrogen"includes "nitrogen" includesa asubstituted substitutednitrogen. nitrogen.AsAs an an example, example, in a in a saturated saturated or partially or partially unsaturated unsaturated

ring having ring having0-3 0-3heteroatoms heteroatoms selected selected fromfrom oxygen, oxygen, sulfur sulfur or nitrogen, or nitrogen, the nitrogen the nitrogen may be may N (as be N (as in 3,4-dihydro-2H-pyrrolyl), in NHin(aspyrrolidinyl), 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or(as or +NR *NRin (as in N-substituted N-substituted pyrrolidinyl). pyrrolidinyl).

[0164] A heterocyclic

[0164] A heterocyclic ring ring can be can be attached attached to its pendant group atgroup to its pendant at any heteroatom any heteroatom or carbon or carbon atomthat atom thatresults results in in aa stable stable structure structure and and any anyofofthe thering ringatoms atomscancan be be optionally optionally substituted. substituted.

Examples Examples of of such such saturated saturated or partially or partially unsaturated unsaturated heterocyclic heterocyclic radicals radicals include, include, without without

limitation, tetrahydrofuranyl, limitation, tetrahydrothiophenyl tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, pyrrolidinyl, piperidinyl, piperidinyl, pyrrolinyl, pyrrolinyl,

tetrahydroquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroquinolinyl, oxazolidinyl, oxazolidinyl, piperazinyl, piperazinyl,

dioxanyl, dioxolanyl, dioxanyl, dioxolanyl,diazepinyl, diazepinyl,oxazepinyl, oxazepinyl, thiazepinyl, thiazepinyl, morpholinyl, morpholinyl, and quinuclidinyl. and quinuclidinyl. The The terms "heterocycle," terms "heterocycle,""heterocyclyl," "heterocyclyl," "heterocyclyl "heterocyclyl ring," ring," "heterocyclic "heterocyclic group," group," "heterocyclic "heterocyclic

moiety,"and moiety," and"heterocyclic "heterocyclic radical," radical," areare used used interchangeably interchangeably herein, herein, and include and also also include groupsgroups in in whicha aheterocyclyl which heterocyclylring ring is isfused fusedtotooneone or or more more aryl, aryl, heteroaryl, heteroaryl, or cycloaliphatic or cycloaliphatic rings, rings, suchsuch

as indolinyl, as 3H-indolyl,chromanyl, indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, phenanthridinyl, or tetrahydroquinolinyl, or tetrahydroquinolinyl, where where the the radical radical

or point or of attachment point of attachmentisisononthe theheterocyclyl heterocyclyl ring.A A ring. heterocyclyl heterocyclyl group group may may be be or mono- mono- or bicyclic. The bicyclic. term"heterocyclylalkyl" The term "heterocyclylalkyl" refers refers to to an an alkyl alkyl group group substituted substituted by a by a heterocyclyl, heterocyclyl,

whereinthe wherein thealkyl alkyland andheterocyclyl heterocyclyl portions portions independently independently are optionally are optionally substituted. substituted.

[0165] As used

[0165] used herein, As herein, the term term "partially the"partially unsaturated" unsaturated" refers refers to to moiety a ring moiety a ring that that includes includes

at least at least one one double or triple double or triple bond. bond. The Theterm term"partially "partiallyunsaturated" unsaturated" is intended is intended to encompass to encompass

rings having rings havingmultiple multiplesites sitesofofunsaturation, unsaturation,but butisisnot notintended intended to to include include aryl aryl or or heteroaryl heteroaryl

moieties, as moieties, as herein hereindefined. defined.

[0166] As described

[0166] As described herein, herein, compounds compounds of the of the invention invention maymay contain contain "optionally "optionally

substituted" moieties. substituted" moieties. InIngeneral, general,thetheterm term "substituted," "substituted," whether whether preceded preceded by theby the term term "optionally" orornot, "optionally" not, means means thatoneone that or or more more hydrogens hydrogens of theofdesignated the designated moiety moiety are replaced are replaced

with aa suitable with suitable substituent. substituent. Unless Unlessotherwise otherwise indicated, indicated, an "optionally an "optionally substituted" substituted" groupgroup may may haveaa suitable have suitable substituent substituentatateach eachsubstitutable substitutableposition positionofofthethegroup, group,andand when when more more than than one one position in position in any anygiven givenstructure structuremay may be be substituted substituted withwith moremore than than one substituent one substituent selected selected from from a specified a group, the specified group, thesubstituent substituentmay maybe be either either thethe same same or different or different at every at every position. position.

Combinations Combinations of of substituents substituents envisioned envisioned by this by this invention invention are preferably are preferably those those that result that result in thein the formationofofstable formation stableororchemically chemically feasible feasible compounds. compounds. The"stable," The term term "stable," as used as used herein, herein, refers refers to compounds to compounds that that areare notnot substantially substantially altered altered when when subjected subjected to conditions to conditions to allow to allow for for their their production,detection, production, detection,and, and,inincertain certainembodiments, embodiments, their their recovery, recovery, purification, purification, andfor and use useone for one or more or ofthe more of thepurposes purposes disclosed disclosed herein. herein.

34

1004799942

[0167] Suitable

[0167] Suitable monovalent monovalent substituents substituents on a substitutable on a substitutable carbon carbon atom of anatom of an "optionally "optionally 2023206094 18 Jul 2023

substituted" group substituted" groupare areindependently independentlyhalogen; -(CH)-4R°; -(CH2)o-40R; -(CH2)-4R; halogen; -O(CH2)o-4R°, -(CH)-4OR°; -O(CH)-4R°, -0- -0 -(CH2)o-4CH(OR°)2;-(CH)-4SR°; (CH2)o4C(O)OR°;-(CH)-4CH(OR°);; (CH)-4C(O)OR°; -(CH2)o-4SR; -(CH2)o-4Ph, -(CH)-4Ph, which which maymay be be substituted substituted

with R°; with R°; -(CH2)o-40(CH2)o-Ph which -(CH2)-4O(CH)0-1Ph which maymay be substitutedwith be substituted withR°; R°;-CH=CHPh, -CH=CHPh, which which may may be be substituted with substituted withR°; R°;-(CH2)o-40(CH2)o-i-pyridyl whichmay -(CH)-4O(CH)0-1-pyridyl which may be be substituted with substituted with R°; R°; -NO; -N02;-CN; -CN; -N3; -(CH)-N(R°); -N; -(CH2)o-4N(R°)2; -(CH2)o-4N(R°)C(O)R; -(CH)-4N(R°)C(O)R°; -N(R°)C(S)R;-(CH)-4N(R°)C(O)NR°; -N(R°)C(S)R°; -(CH2)o-4N(R°)C(O)NR°2;

-N(R°)C(S)NR°2; -(CH)-4N(R°)C(O)OR°; -N(R°)C(S)NR°; -(CH2)o-4N(R°)C(O)OR;-N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)R;-N(R°)N(R°)C(O)NR°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR; -(CH)-4C(O)R°; -N(R°)N(R°)C(O)OR°; -(CH2)o-4C(O)R; -C(S)R°; -C(S)R; -(CH)-4C(O)OR°; -(CH2)-4C(O)OR;-(CH)-4C(O)SR°; -(CH2)-4C(O)SR°; -(CH)-4C(O)OSiR³; -(CH2)o-40C(O)R; -(CH2)o-4C(O)OSiR°3;-(CH)-4OC(O)R°; -OC(O)(CH2)o-4SR°-; -OC(O)(CH)-4SRº; -(CH)- -(CH2)o -(CH2)o-4SC(O)R; -(CH)-4SC(O)R°;

-C(S)NR°2; -C(S)SR°; 4C(O)NR2; -C(S)NR°; 4C(O)NR°; -C(S)SR°; -SC(S)SR°, -(CH2)o-40C(O)NR°2;-C(O)N(OR°)R°; -SC(S)SR°, -(CH2)-4OC(O)NR°; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R; -C(O)C(O)R°; -C(NOR)R°; -C(O)CHC(O)R°; -C(NOR°)R°; -(CH2)-4SSR; -(CH)-4SSR°; -(CH2)-4S(O)2R; -(CH)-4S(O)R°; -(CH2)o -(CH)-

-(CH2)o-40S(O)2R;-S(O)2NR°; 4S(O)20R; -(CH)-4OS(O)R°; 4S(O)OR°; -S(O)2NR2; -(CH2)o-4S(O)R; -(CH)-4S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)NR°;

-N(R°)S(O)2R; -N(OR°)R°; -N(R°)S(O)R°; -N(OR)R°; -C(NH)NR°2; -C(NH)NR2; -P(O)R°; -P(O)2R; -P(O)R°; -P(O)R°2; -OP(O)R°; -OP(O)R°2;-OP(O)(OR°); -OP(O)(OR°)2;

SiR°3;-(C1-4 SiR°; straightororbranched -(C1-4straight branched alkylene)O-N(R)2; alkylene)O-N(R°)2; or -(C1-4 or -(C1-4 straight straight or branched or branched

alkylene)C(O)O-N(R)2,wherein alkylene)C(O)O-N(R°), each wherein each R° R maymay be be substitutedasasdefined substituted defined below belowand andisis independently hydrogen, independently hydrogen, C1-6 C1-6aliphatic, aliphatic,-CH2Ph, -CH2Ph,-O(CH2)o-iPh, -CH2-(5-6 -O(CH)-1Ph, -CH-(5-6 membered membered

heteroaryl ring), heteroaryl ring), or or aa 5-6-membered saturated, 5-6-membered saturated, partially partially unsaturated, unsaturated, or aryl or aryl ring ring having having 0-4 0-4 heteroatomsindependently heteroatoms independently selected selected from from nitrogen, nitrogen, oxygen, oxygen, or sulfur, or sulfur, or, notwithstanding or, notwithstanding the the definition above, definition above,two twoindependent independent occurrences occurrences oftaken of R°, R, taken together together with intervening with their their intervening atom(s), form atom(s), forma a3-12-membered 3-12-membered saturated, saturated, partially partially unsaturated, unsaturated, or arylormono- aryl or mono- or bicyclic bicyclic ring ring having0-4 having 0-4heteroatoms heteroatoms independently independently selected selected from nitrogen, from nitrogen, oxygen,oxygen, or which or sulfur, sulfur,maywhich be may be substituted as substituted as defined definedbelow. below.

[0168] Suitable

[0168] Suitable monovalent monovalent substituents substituents on on R° R (or(or thering the ring formed formed by by taking taking two two independentoccurrences independent occurrences of together of R° R together with with theirtheir intervening intervening atoms), atoms), are independently are independently

halogen, -(CH2)-2R*, halogen, -(CH)-R, -(haloR*), -(haloR), -(CH2)o-20H, -(CH)-2OH,-(CH2)o-20R*, -(CH)-OR, -(CH2)o -(CH)- -O(haloR*), -CN, 2CH(OR*)2, -O(haloR), 2CH(OR°), -CN, -N, -N3,-(CH2)-2C(O)R*, -(CH2)-2C(O)OH, -(CH)-2C(O)R, -(CH)-2C(O)OH, -(CH2)o-2C(O)OR*, -(CH)-2C(O)OR,

-(CH2)o-2SR*, -(CH)-2SH, -(CH)-2SR, -(CH2)o-2SH, -(CH)-2NH, -(CH2)o-2NH2,-(CH2)o-2NHR*, -(CH2)o-2NR*2,-NO2,-SiR*3, -(CH)-2NHR, -(CH)-2NR, -NO, -SiR°3, -OSiR* 3-C(O)SR, -OSiR°, , -C(O)SR*, -(C1-4straight -(C1-4 straightororbranched branchedalkylene)C(O)OR, alkylene)C(O)OR*, or or -SSR'; -SSR; wherein wherein each each R® R* is unsubstituted is or where unsubstituted or wherepreceded precededby by "halo" "halo" is substituted is substituted onlyonly with with one one or or halogens, more more halogens, and and is independently is independently selected selectedfrom fromC1-4aliphatic, -CH2Ph, C1-4 aliphatic, -O(CH2)o-iPh, -CHPh, -O(CH)-Ph, orora a5-6-membered 5-6-membered saturated, partially saturated, partially unsaturated, or aryl unsaturated, or aryl ring ring having having0-4 0-4heteroatoms heteroatoms independently independently selected selected from from nitrogen, oxygen, nitrogen, oxygen,ororsulfur. sulfur.Suitable Suitabledivalent divalent substituents substituents on on a saturated a saturated carbon carbon atom atom of R° of R° include =0 include and =S. =0 and =S.

35

1004799942

[0169] Suitable

[0169] Suitable divalent divalent substituents substituents on a saturated on a saturated carbon carbon atom of atom of an "optionally an "optionally 2023206094 18 Jul 2023

substituted" group substituted" groupinclude includethe following: the =0,=0, following: =S,=S, =NNR*2, =NNR*2,=NNHC(O)R*, =NNHC(O)OR*, =NNHC(O)R*, =NNHC(O)OR*,

=NNHS(O)2R*, =NNHS(O)R*, =NR*, =NR*, =NOR*, =NOR*, -O(C(R*2))2-3-, -O(C(R*2))2-30-, or -S(C(R*2))2-3S-, wherein each each or -S(C(R*2))2-3S-,wherein independent independent

occurrenceofofR*R*isisselected occurrence selectedfrom from hydrogen,C1-6aliphatic hydrogen, which C1-6 aliphatic which may bemay be substituted substituted as defined as defined

below,ororananunsubstituted below, unsubstituted5-6-membered 5-6-membered saturated, saturated, partially partially unsaturated, unsaturated, or aryl or arylhaving ring ring having 0- 0 4 heteroatoms 4 heteroatomsindependently independently selected selected from from nitrogen, nitrogen, oxygen, oxygen, or sulfur. or sulfur. Suitable Suitable divalentdivalent

substituents that substituents that are are bound boundtotovicinal vicinalsubstitutable substitutablecarbons carbons of of an an "optionally "optionally substituted" substituted" group group

include: -O(CR*2)2-30-, include: whereineach -O(CR*2)-O-, wherein eachindependent independentoccurrence occurrenceofofR*R*isis selected selected from from hydrogen, hydrogen,

C1-6 aliphatic C1-6 whichmay aliphatic which maybe be substituted substituted as defined as defined below, below, or anorunsubstituted an unsubstituted 5-6-membered 5-6-membered

saturated, partially saturated, partially unsaturated, or aryl unsaturated, or aryl ring ring having having0-4 0-4heteroatoms heteroatoms independently independently selected selected from from nitrogen, oxygen, nitrogen, oxygen,ororsulfur. sulfur.

[0170]

[0170] Suitable substituents Suitable on theon substituents aliphatic group of the aliphatic R* include group halogen,halogen, of R* include -R*, -(haloR*), -R°, -(haloR),-OH, -OH,-OR*, -OR°,-O(haloR*), -O(haloR),-CN, -C(O)OH, -CN, -C(O)OH,-C(O)OR*, -C(O)OR, -NH2,-NHR*, -NR'2, -NH, -NHR, -NR°2,

or -N02,wherein or -NO, wherein eacheach R® isR* is unsubstituted unsubstituted or where or where preceded preceded byis"halo" by "halo" is substituted substituted only withonly with one or one or more more halogens, halogens, and and is isindependently independentlyC1-4aliphatic, -CH2Ph, C1-4 aliphatic, -CHPh,-O(CH2)o-Ph, 5-6 or aa 5-6- -O(CH)-1Ph, or

membered membered saturated, saturated, partially partially unsaturated, unsaturated, or aryl or aryl ring ring having having 0-4 heteroatoms 0-4 heteroatoms independently independently

selected from selected fromnitrogen, nitrogen,oxygen, oxygen, or or sulfur. sulfur.

[0171] Suitable

[0171] Suitable substituents substituents on a substitutable on a substitutable nitrogen nitrogen of an "optionally of an "optionally substituted" substituted" group group include -RT, include -R,-NR -NR,2,-C(O)RT, -C(O)OR, -C(0)C(O)R, -C(O)R, -C(O)OR+, -C(O)C(O)R,-C(O)CHC(O)R, -C(O)CH2C(O)R, -S(O)2NRi2,-C(S)NRt2,-C(NH)NRt2, -S(O)2R, -S(O)NR, -S(O)R, or -N(R)S(O) -C(S)NR, -C(NH)NR, or -N(R¹)S(O)R; wherein each Reach 2 R; wherein is RT is independentlyhydrogen, independently hydrogen, C1-6C1-6aliphatic which aliphatic which may may be be substituted substituted as defined as defined below, below, unsubstituted-OPh, unsubstituted -OPh,or or an an unsubstituted unsubstituted 5-6-membered 5-6-membered saturated, saturated, partially partially unsaturated, unsaturated, or aryl or aryl ring having ring having0-4 0-4heteroatoms heteroatoms independently independently selected selected from nitrogen, from nitrogen, oxygen,oxygen, or or, or sulfur, sulfur, or, notwithstandingthethedefinition notwithstanding above, definitionabove, twotwo independent independent occurrences occurrences of RT,together of R, taken taken together with with their intervening their atom(s)form intervening atom(s) forman an unsubstituted unsubstituted 3-12-membered 3-12-membered saturated, saturated, partiallypartially unsaturated, unsaturated,

or aryl or aryl mono- mono- oror bicyclicring bicyclic ringhaving having 0-40-4 heteroatoms heteroatoms independently independently selectedselected from nitrogen, from nitrogen,

oxygen,ororsulfur. oxygen, sulfur.

[0172] Suitable

[0172] Suitable substituents substituents on aliphatic on the the aliphatic group group of R of are R are independently independently halogen, halogen,

-R*, -(haloR*), -R°, -(haloR),-OH, -OH, -OR*, -OR°, -O(haloR*), -O(haloR), -CN, -CN, -C(O)OH, -C(O)OR*,-NH, -C(O)OH, -C(O)OR, -NH2, -NHR*, -NHR, -NR'2, -NR°2,

or -NO, or -N02,wherein wherein eacheach R® isR* is unsubstituted unsubstituted or where or where precededpreceded by "halo"by is "halo" is substituted substituted only with only with one or one or more more halogens, halogens, and andisis independently independently C1-4 C1-4aliphatic, aliphatic,-CH2Ph, -O(CH2)o-iPh, -CHPh, -O(CH)-1Ph, or aor5-6- a 5-6 membered membered saturated, saturated, partially partially unsaturated, unsaturated, or ring or aryl aryl having ring having 0-4 heteroatoms 0-4 heteroatoms independently independently

selected from selected fromnitrogen, nitrogen,oxygen, oxygen, or or sulfur. sulfur.

[0173] The term

[0173] term "co-crystal" The "co-crystal" refers refers to to a molecular a molecular complex complex of of anorionized an ionized or non-ionized non-ionized

Compound Compound 1 (or 1 (or any any otherother compound compound disclosed disclosed herein) herein) andmore and one or onenon-ionized or more non-ionized co-crystal co-crystal

36

1004799942

formers(such formers (suchasasa apharmaceutically pharmaceutically acceptable acceptable salt)salt) connected connected through through non-covalent non-covalent 2023206094 18 Jul 2023

interactions. interactions.

[0174] used herein, As herein,

[0174] As used the term acceptableacceptable term "pharmaceutically the"pharmaceutically salt" refers to refers salt" to those those salts salts whichare, which are, within withinthe thescope scopeof of sound sound medical medical judgment, judgment, suitable suitable forinuse for use in contact contact with with the the tissues of tissues of humans and humans and lower lower animals animals without without undue undue toxicity, toxicity, irritation, irritation, allergic allergic response response and and the the like, and like, are commensurate and are commensurate withwith a reasonable a reasonable benefit/risk benefit/risk ratio. ratio. Pharmaceutically Pharmaceutically acceptable acceptable

salts are salts are well well known known ininthe theart. art. For Forexample, example, S. M. S. M. Berge Berge et al., et al., describe describe pharmaceutically pharmaceutically

acceptablesalts acceptable salts in in detail detail in in J.J.Pharmaceutical Sciences,1977, Pharmaceutical Sciences, 1977, 66,66, 1-19, 1-19, as does as does the Handbook the Handbook of of PharmaceuticalSalts: Pharmaceutical Salts:Properties, Properties,Selection, Selection, andand Use, Use, 2nd Revised 2 Revised Edition, Edition, P. Heinrich P. Heinrich Stahl Stahl and and CamilleG.G.Wermuth, Camille Wermuth,Eds.Eds. Wiley, Wiley, April,April, 2011, 2011, each each of of is which which is incorporated incorporated herein byherein by reference. Pharmaceutically reference. Pharmaceutically acceptable acceptable saltssalts of the of the compounds compounds of thisof this invention invention includeinclude those those derived from derived fromsuitable suitableinorganic inorganic andand organic organic acids acids and bases. and bases. Examples Examples of pharmaceutically of pharmaceutically

acceptable, nontoxic acceptable, nontoxicacid acidaddition addition saltsarearesalts salts saltsofofananamino amino group group formed formed with inorganic with inorganic acids acids such as such as hydrochloric hydrochloricacid, acid,hydrobromic hydrobromic acid,acid, phosphoric phosphoric acid, acid, sulfuric sulfuric acidperchloric acid and and perchloric acid acid or with or organicacids with organic acidssuch suchas asacetic aceticacid, acid,oxalic oxalicacid, acid,maleic maleic acid, acid, tartaricacid, tartaric acid,citric citric acid, acid, succinic acid succinic acid or or malonic malonicacid acidororbyby using using other other methods methods used used in theinart thesuch art such as ionasexchange. ion exchange. Otherpharmaceutically Other pharmaceutically acceptable acceptable salts salts include include adipate, adipate, alginate, alginate, ascorbate, ascorbate, aspartate, aspartate,

benzenesulfonate,benzoate, benzenesulfonate, benzoate, bisulfate, bisulfate, borate, borate, butyrate, butyrate, camphorate, camphorate, camphorsulfonate, camphorsulfonate, citrate,citrate,

cyclopentanepropionate, cyclopentanepropionate, digluconate, digluconate, dodecylsulfate, dodecylsulfate, ethanesulfonate, ethanesulfonate, formate, formate, fumarate, fumarate,

glucoheptonate,glycerophosphate, glucoheptonate, glycerophosphate, gluconate, gluconate, hemisulfate, hemisulfate, heptanoate, heptanoate, hexanoate, hexanoate, hydroiodide, hydroiodide,

2-hydroxy-ethanesulfonate, 2-hydroxy-ethanesulfonate, lactobionate, lactobionate, lactate, lactate, laurate, laurate, lauryl lauryl sulfate, sulfate, malate, malate, maleate, maleate,

malonate,methanesulfonate, malonate, methanesulfonate, 2-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nicotinate, nitrate, nitrate, oleate, oleate, oxalate, oxalate,

palmitate, pamoate, palmitate, pamoate,pectinate, pectinate,persulfate, persulfate,3-phenylpropionate, 3-phenylpropionate, phosphate, phosphate, pivalate, pivalate, propionate, propionate,

stearate, succinate, stearate, sulfate, tartrate, succinate, sulfate, tartrate,thiocyanate, thiocyanate,p-toluenesulfonate, undecanoate, p-toluenesulfonate, undecanoate, valerate valerate salts, salts,

and the and the like. like.

[0175] Salts Salts

[0175] derived derived from appropriate from appropriate bases include bases include metal metal ions ions (including (including aluminum, aluminum, zinc, zinc, alkali metals, alkali alkaline earth metals, alkaline earth metals), metals), ammonium ammonium and N+(C1-4alkyl)4salts. and N(C-alkyl) Representative salts. Representative alkali alkali or alkaline or earth metal alkaline earth metal salts salts include include sodium, sodium,lithium, lithium,potassium, potassium, calcium, calcium, magnesium, magnesium, and the and the like. Further like. Further pharmaceutically acceptable pharmaceutically acceptable salts salts include, include, when when appropriate, appropriate, those those derived derived from from nontoxic ammonium, nontoxic quaternaryammonium, ammonium, quaternary ammonium, and and primary, primary, secondary secondary or tertiaryamine or tertiary aminecations, cations, including but including butnot notlimited limitedtotothose thosederived derivedfrom from natural natural or non-naturally-occurring or non-naturally-occurring amino amino acids. acids. Representativeamine Representative amine or or ammonium-based ammonium-based salts include salts include but are but are not to not limited limited those to those from derived derived from arginine, betaine, arginine, betaine, hydrabamine, hydrabamine, choline, choline, diethylamine, diethylamine, lysine, lysine, benzathine, benzathine, 2-(diethylamino) 2-(diethylamino)-

ethanol, ethanolamine, ethanol, ethanolamine,1-(2-hydroxyethyl)-pyrrolidine 1-(2-hydroxyethyl)-pyrrolidine, diethanolamine, diethanolamine, ammonia,ammonia, deanol, N- deanol, N

37

1004799942

methyl-glucamine, methyl-glucamine, tromethamine, tromethamine, triethanolamine, triethanolamine, 4-(2-hydroxyethyl)-morpholine, 4-(2-hydroxyethyl)-morpholine, 2023206094 18 Jul 2023

1H-imidazole,ethylenediamine, 1H-imidazole, ethylenediamine, piperazine, piperazine, procaine, procaine, and benethamine. and benethamine.

[0176] UnlessUnless

[0176] otherwise stated, stated, otherwise structures structures depicted depicted herein are also are herein meant includetoall alsotomeant include all isomeric(e.g., isomeric (e.g., enantiomeric, enantiomeric,diastereomeric, diastereomeric,andand geometric geometric (or conformational)) (or conformational)) forms forms of the of the structure; for structure; for example, theR Rand example, the andS configurations S configurations for for eacheach asymmetric asymmetric center,center, Z and Z and E E double double bondisomers, bond isomers,andand Z and Z and E conformational E conformational isomers. isomers. Therefore, Therefore, single stereochemical single stereochemical isomers asisomers as well as well as enantiomeric, enantiomeric,diastereomeric, diastereomeric, andand geometric geometric (or conformational) (or conformational) mixtures mixtures of the present of the present

compounds compounds are are within within the the scope scope of invention. of the the invention. UnlessUnless otherwise otherwise stated, stated, all tautomeric all tautomeric forms forms of the of the compounds of the compounds of the invention invention are are within within the scope the scope ofinvention. of the the invention. Additionally, Additionally, unless unless otherwisestated, otherwise stated, structures structuresdepicted depictedherein hereinarearealso alsomeant meant to include to include compounds compounds that differ that differ only only in the in the presence ofone presence of oneorormore more isotopically isotopically enriched enriched atoms. atoms. For example, For example, compounds compounds having thehaving the present structures present structures including includingthe thereplacement replacement of hydrogen of hydrogen by deuterium by deuterium or tritium, or tritium, or the or the replacementofofa acarbon replacement carbon by by a 1C- a ¹³C- or 14C-enriched or ¹C-enriched carboncarbon are within are within the ofscope the scope this of this invention. invention.

Suchcompounds Such compounds are useful, are useful, for example, for example, as analytical as analytical tools,tools, as probes as probes in biological in biological assays, assays, or as or as therapeutic agents therapeutic agentsininaccordance accordance with with the the present present invention. invention.

term "reaction The "reaction

[0177] The term

[0177] conditions" conditions" is intended to refer to refer to is intended to the physical the physical and/or and/or environmentalconditions environmental conditions under under which which a chemical a chemical reaction reaction proceeds. proceeds. The termThe termconditions "under "under conditions sufficient to" sufficient to" or or "under reactionconditions "under reaction conditionssufficient sufficientto"to"isisintended intendedto torefer refertotothe thereaction reaction conditions under conditions underwhich which thethe desired desired chemical chemical reaction reaction can proceed. can proceed. Examples Examples of of reaction reaction conditions include, conditions include,but butare arenot notlimited limitedto, to,one oneorormore moreof of following: following: reaction reaction temperature, temperature,

solvent, pH, solvent, pH, pressure, pressure, reaction reactiontime, time,mole mole ratioof of ratio reactants,thethepresence reactants, presence ofbase of a a base or acid, or acid, or or catalyst, radiation, catalyst, radiation, concentration, etc. Reaction concentration, etc. Reactionconditions conditions maymay be named be named afterparticular after the the particular chemicalreaction chemical reactionininwhich whichthethe conditions conditions are are employed, employed, suchcoupling such as, as, coupling conditions, conditions,

hydrogenation hydrogenation conditions, conditions, acylation acylation conditions, conditions, reduction reduction conditions, conditions, etc. Reaction etc. Reaction conditions conditions

for most for reactionsare most reactions aregenerally generallyknown known to those to those skilled skilled in the in the art art or or cancan be readily be readily obtained obtained from from the literature. the literature. Exemplary reaction Exemplary reaction conditions conditions sufficient sufficient for for performing performing the chemical the chemical

transformationsprovided transformations provided herein herein can can be found be found throughout, throughout, and inand in particular, particular, the examples the examples

below.ItItisis also below. also contemplated contemplated that that thethe reaction reaction conditions conditions can can include include reagents reagents in addition in addition to to those listed in the specific reaction. those listed in the specific reaction.

4. General 4. General methods for providing methods for providing thepresent the present compounds compounds

[0178] The The

[0178] present present processes maymay processes be performed be performed using using methods methods disclosed disclosed herein andand herein routine routine

modificationsthereof modifications thereofwhich which will will be be apparent apparent given given the disclosure the disclosure herein herein and methods and methods well well knownininthetheart. known art.Conventional Conventional and and well-known well-known synthetic synthetic methods methods may may be used in be used intoaddition addition to the teachings the herein. The teachings herein. The synthesis synthesis of of typical typical compounds compounds described described herein,herein, e.g. compounds e.g. compounds

38

1004799942

havingstructures having structuresdescribed describedby by Compound Compound 1, or other 1, or other formulas formulas or compounds or compounds disclosed disclosed herein herein 2023206094 18 Jul 2023

(i.e. I,I,G-1, (i.e. G-1,G-1-a, G-1-a, G-2, G-2-a,G-2-b, G-2, G-2-a, G-2-b, G-3, G-3, G-3-b, G-3-b, G-4, G-4, G-4-a, G-4-a, G-4-b,G-4-b, G-5, G-6, G-5, G-5-a, G-5-a, G-6- G-6, G-6 a, G-7, a, G-7-a,G-8, G-7, G-7-a, G-8,G-8-a, G-8-a, G-8-b, G-8-b, G-9, G-9, G-9-a,G-9-a, G-10,G-12, G-10, G-11, G-11,G-13, G-12, G-13,etc.) G-13-a, G-13-a, may beetc.) may be accomplished accomplished as as described described in the in the following following examples. examples. If available, If available, reagents reagents may be may be purchased purchased

commercially,e.g. commercially, e.g.from from Sigma Sigma Aldrich Aldrich or other or other chemical chemical suppliers. suppliers.

[0179] Typical

[0179] Typical embodiments embodiments of compounds of compounds in accordance in accordance withpresent with the the present disclosure disclosure maymay

be synthesized be synthesizedusing usingthethegeneral general reaction reaction schemes schemes described described below.below. It will Itbewill be apparent apparent given given the the description herein description hereinthat thatthe thegeneral generalschemes schemesmaymay be altered be altered by substitution by substitution ofstarting of the the starting materials with materials withother othermaterials materialshaving having similar similar structures structures to to result result in in products products that that areare

correspondinglydifferent. correspondingly different.Descriptions Descriptions of syntheses of syntheses follow follow to provide to provide numerous numerous examples examples of of howthe how thestarting startingmaterials materialsmaymay vary vary to provide to provide corresponding corresponding products. products. Given a Given desireda product desired product for which for thesubstituent which the substituentgroups groupsareare defined, defined, thethe necessary necessary starting starting materials materials generally generally may may be be determinedbybyinspection. determined inspection. Starting Starting materials materials are typically are typically obtained obtained from from commercial commercial sources sources or or synthesized using synthesized using published publishedmethods. For synthesizing methods. For synthesizing compounds whichare compounds which areembodiments embodimentsofof the present the disclosure, inspection present disclosure, inspectionofofthe thestructure structureofofthe thecompound compoundto betosynthesized be synthesized will will providethe provide theidentity identity ofofeach eachsubstituent substituentgroup. group.TheThe identity identity of the of the final final product product will will generally generally

render apparent render apparentthe theidentity identityofofthe thenecessary necessary startingmaterials starting materials by by a simple a simple process process of inspection, of inspection,

given the given the examples examplesherein. herein.

[0180] The compounds

[0180] The compounds of this disclosure of this disclosure can be from can be prepared prepared from readily readilystarting available available starting materials using, materials using, for for example, example,thethefollowing following general general methods methods and procedures. and procedures. It will It be will be appreciatedthat appreciated thatwhere wheretypical typicalor orpreferred preferred process process conditions conditions (i.e., (i.e., reaction reaction temperatures, temperatures, times, times,

moleratios mole ratios ofofreactants, reactants, solvents, solvents, pressures, pressures, etc.) etc.) are are given, given, other otherprocess processand and purification purification

conditionscan conditions canalso alsobebeused usedunless unless otherwise otherwise stated. stated. Optimum Optimum reaction reaction conditions conditions may vary may vary with the with the particular particular reactants reactants or or solvent solventused, used,but butsuch suchconditions conditions cancan be determined be determined by by one one skilled in skilled in the the art artby by routine routine optimization procedures. optimization procedures.

[0181] Additionally,

[0181] Additionally, asbewill as will be apparent apparent to skilled to those those skilled in the in theconventional art, art, conventional protecting protecting

groupsmay groups maybe be necessary necessary to prevent to prevent certain certain functional functional groups groups from undergoing from undergoing undesiredundesired

reactions. Suitable reactions. Suitableprotecting protectinggroups groups forfor various various functional functional groups groups as well as well as suitable as suitable conditions conditions

for protecting for anddeprotecting protecting and deprotectingparticular particularfunctional functional groups groups are are wellwell known known in thein the For art. art. For example,numerous example, numerous protecting protecting groups groups are described are described in T. in T. W. W. Greene Greene and G. M.and G.(1999) Wuts M. Wuts (1999) Protecting Groups Protecting Groups in in Organic Organic Synthesis, Synthesis, 3rd Edition, 3rd Edition, Wiley, Wiley, NewandYork, New York, and references references cited cited therein. therein.

[0182] the the Furthermore,

[0182] Furthermore, compounds compounds of this of this disclosure disclosure may may contain contain one or or one more more chiral chiral

centers. Accordingly, centers. Accordingly,if if desired,such desired, such compounds compounds can becan be prepared prepared or isolated or isolated as pure as pure stereoisomers,i.e., stereoisomers, i.e., as as individual enantiomersor or individual enantiomers diastereomers diastereomers orstereoisomer-enriched or as as stereoisomer-enriched

39

1004799942

mixtures. All mixtures. Allsuch such stereoisomers stereoisomers (and(and enriched enriched mixtures) mixtures) are included are included within within theofscope the scope this of this 2023206094 18 Jul 2023

disclosure, unless disclosure, unless otherwise otherwiseindicated. indicated.PurePure stereoisomers stereoisomers (or enriched (or enriched mixtures) mixtures) may be may be preparedusing, prepared using,for forexample, example, optically optically active active starting starting materials materials or stereoselective or stereoselective reagents reagents well well-

knownin inthetheart. known art.Alternatively, Alternatively,racemic racemic mixtures mixtures of such of such compounds compounds can be separated can be separated using, using, for example, for chiralcolumn example, chiral column chromatography, chromatography, chiralchiral resolving resolving agents,agents, and theand the like. like.

[0183] The The

[0183] starting starting materialsfor materials the following forthe aregenerally reactions are following reactions generally known compounds known or compounds or

can be can be prepared preparedbybyknown known procedures procedures or obvious or obvious modifications modifications thereof. thereof. For many For example, example, of many of the starting the starting materials are available materials are available from fromcommercial commercial suppliers suppliers such such as Aldrich as Aldrich Chemical Chemical Co. Co. (Milwaukee, Wisconsin, (Milwaukee, Wisconsin, USA), USA),Bachem Bachem (Torrance,California, (Torrance, California, USA), USA),Emka-Chemce Emka-Chemce or Sigma or Sigma

(St. Louis, (St. Louis, Missouri, USA).Others Missouri, USA). Others may may be be prepared prepared by procedures by procedures or modifications or obvious obvious modifications thereof, described thereof, describedininstandard standardreference referencetexts textssuch such as as Fieser Fieser andand Fieser's Fieser's Reagents Reagents for Organic for Organic

Synthesis, Volumes Synthesis, 1-15 (John Volumes 1-15 (John Wiley, Wiley, and and Sons, Sons, 1991), 1991), Rodd's Rodd's Chemistry Chemistry of of Carbon Carbon

Compounds,Volumes Compounds, Volumes 1-5,andand 1-5, Supplementals Supplementals (ElsevierScience (Elsevier SciencePublishers, Publishers, 1989) 1989) organic organic Reactions, Volumes Reactions, 1-40 (John Volumes 1-40 (John Wiley, Wiley, and and Sons, Sons, 1991), 1991), March's March's Advanced OrganicChemistry, Advanced Organic Chemistry, (John Wiley, and Sons, (John Edition, 2001), Sons, 55thEdition, 2001), and and Larock's Larock'sComprehensive Organic Comprehensive Organic

Transformations Transformations (VCH (VCH Publishers Publishers Inc., Inc., 1989).1989).

[0184] The terms

[0184] The terms "solvent," "inert "inert "solvent," solvent"solvent" organicorganic refer to refer "inert solvent" or "inertorsolvent" to a solvent a solvent inert inert underthe under theconditions conditionsofofthe thereaction reactionbeing being described described in conjunction in conjunction therewith therewith (including, (including, for for example,benzene, example, benzene, toluene, toluene, acetonitrile,tetrahydrofuran acetonitrile, tetrahydrofuran ("THF"), ("THF"), 2-methyltetrahydrofuran 2-methyltetrahydrofuran

("MeTHF"),dimethylformamide ("MeTHF"), dimethylformamide ("DMF"), ("DMF"), chloroform, chloroform, methylene methylene chloride chloride (or (or

dichloromethane),diethyl dichloromethane), diethyl ether,methanol, ether, methanol, 2-propanol, 2-propanol, pyridine pyridine andlike). and the the like). UnlessUnless specified specified

to the to the contrary, the solvents contrary, the solvents used usedininthe thereactions reactionsofofthe thepresent presentdisclosure disclosureareareinert inertorganic organic solvents, and solvents, andthe thereactions reactionsare arecarried carriedout outunder underanan inertgas, inert gas,preferably preferably nitrogen. nitrogen.

In each

[0185] In each

[0185] thethe of of exemplary exemplary schemes schemes it may it may be be advantageous to to advantageous separate reaction separatereaction productsfrom products fromoneone another another and/or and/or fromfrom starting starting materials. materials. The desired The desired products products of each of each step or step or series of series of steps steps is is separated and/or purified separated and/or purified (hereinafter (hereinafterseparated) separated)totothe thedesired desireddegree degree of of homogeneity homogeneity by by the the techniques techniques common common in theTypically in the art. art. Typically such separations such separations involve involve multiphaseextraction, multiphase extraction,crystallization crystallizationfrom from a solvent a solvent or or solvent solvent mixture, mixture, distillation, distillation, sublimation, sublimation,

or chromatography. or Chromatography chromatography. Chromatography cancan involveany involve anynumber number of of methods methods including,for including, for example:reverse-phase example: reverse-phase and and normal normal phase;phase; size exclusion; size exclusion; ion exchange; ion exchange; high, and high, medium, medium, low and low pressure liquid pressure liquid chromatography chromatography methods methods and apparatus; and apparatus; smallanalytical; small scale scale analytical; simulated simulated

movingbedbed moving (SMB) (SMB) and preparative and preparative thin thin or or thick thick layer layer chromatography, chromatography, as techniques as well as well as techniques of of small scale small scale thin thin layer layer and andflash flashchromatography. chromatography.

[0186] Another

[0186] Another class class of of separation separation methods methods involves involves treatment treatment of with of a mixture a mixture with a reagent a reagent selected to selected to bind bind toto or or render render otherwise otherwiseseparable separable a desired a desired product, product, unreacted unreacted starting starting material, material,

40

1004799942

reaction by reaction by product, product,ororthe thelike. like. Such Such reagents reagents include include adsorbents adsorbents or absorbents or absorbents such such as as 2023206094 18 Jul 2023

activated carbon, activated carbon,molecular molecular sieves, sieves, ionion exchange exchange media, media, or theorlike. the like. Alternatively, Alternatively, the reagents the reagents

can be can be acids acids inin the the case caseofofaabasic basic material, material, bases basesininthe thecase caseofofananacidic acidicmaterial, material,binding binding reagents such reagents suchasasantibodies, antibodies,binding binding proteins, proteins, selective selective chelators chelators such such as crown as crown ethers, ethers,

liquid/liquid ion liquid/liquid ion extraction extraction reagents reagents(LIX), (LIX),ororthe thelike. like.

[0187] Selection

[0187] Selection of appropriate methodsmethods of appropriate of separation of separation depends depends on on the the nature nature of the of the materials materials involved. For involved. Forexample, example, boiling boiling point, point, and and molecular molecular weightweight in distillation in distillation and sublimation, and sublimation,

presenceororabsence presence absenceof of polar polar functional functional groups groups in chromatography, in chromatography, stability stability of materials of materials in in acidic and acidic and basic basic media mediain in multiphase multiphase extraction, extraction, and and the like. the like. One skilled One skilled inart in the the will art will applyapply techniquesmost techniques most likelytotoachieve likely achieve thethe desired desired separation. separation.

[0188] A single

[0188] A single stereoisomer, stereoisomer, e.g., e.g., an an enantiomer, enantiomer, substantially substantially freestereoisomer free of its of its stereoisomer may may be obtained be obtainedbybyresolution resolutionofofthetheracemic racemic mixture mixture using using a method a method such such as as formation formation of of diastereomersusing diastereomers usingoptically optically active active resolving resolving agents agents (Stereochemistry (Stereochemistry of Carbon of Carbon Compounds, Compounds,

(1962) by (1962) byE.E.L.L.Eliel, Eliel,McGraw McGraw Hill; Hill; Lochmuller, Lochmuller, C. H., C. H., J. (1975) (1975) J. Chromatogr., Chromatogr., 113, 113, 3) 283- 3) 283 302). Racemic 302). Racemic mixtures mixtures of chiral of chiral compounds compounds of the of the disclosure disclosure can be separated can be separated and by and isolated isolated by any suitable any suitable method, method,including: including: (1) (1) formation formation of ionic, of ionic, diastereomeric diastereomeric salts salts with chiral with chiral

compounds compounds and and separation separation by fractional by fractional crystallization crystallization or other or other methods, methods, (2) formation (2) formation of of diastereomericcompounds diastereomeric compounds with with chiral chiral derivatizing derivatizing reagents, reagents, separation separation of the of the diastereomers, diastereomers, and and conversiontotothe conversion thepure purestereoisomers, stereoisomers, andand (3) (3) separation separation of the of the substantially substantially purepure or enriched or enriched

stereoisomersdirectly stereoisomers directlyunder under chiralconditions. chiral conditions.

[0189] Under

[0189] Under method method (1), (1), diastereomeric diastereomeric saltscancanbebeformed salts formedbybyreaction reactionofof enantiomerically enantiomerically pure chiral pure chiral bases basessuch suchasasbrucine, brucine,quinine, quinine,ephedrine, ephedrine, strychnine, strychnine, -methyl-p-phenylethylamine -methyl--phenylethylamine

(amphetamine), (amphetamine), andand the the likelike with with asymmetric asymmetric compounds compounds bearingfunctionality, bearing acidic acidic functionality, such as such as carboxylicacid carboxylic acidand andsulfonic sulfonicacid. acid.TheThe diastereomeric diastereomeric saltssalts may may be be induced induced to separate to separate by by fractional crystallization fractional crystallization or or ionic chromatography. ionic chromatography. For For separation separation ofoptical of the the optical isomers isomers of of aminocompounds, amino compounds, addition addition of chiral of chiral carboxylic carboxylic or sulfonic or sulfonic acids,acids, such such as as camphorsulfonic camphorsulfonic acid, acid, tartaric acid, tartaric acid, mandelic acid, or mandelic acid, or lactic lactic acid can result acid can result in in formation ofthe formation of thediastereomeric diastereomeric salts. salts.

Alternatively,

[0190] Alternatively,

[0190] by method (2), the(2), by method the substrate substrate to be resolved to be resolved is reacted with onewith is reacted one enantiomerofof enantiomer a a chiralcompound chiral compound to form to form a diastereomeric a diastereomeric pair (Eliel, pair (Eliel, E. andE.Wilen, and Wilen, S. S. (1994) (1994) Stereochemistry of Stereochemistry of Organic Organic Compounds, JohnWiley Compounds, John Wiley& & Sons,Inc., Sons, Inc., p. p. 322). 322). Diastereomeric Diastereomeric compoundscan compounds canbebeformed formedbybyreacting reacting asymmetric asymmetriccompounds compounds with with enantiomericallypure enantiomerically purechiral chiral derivatizing reagents, derivatizing reagents, such suchasasmenthyl menthyl derivatives, derivatives, followed followed by separation by separation of theofdiastereomers the diastereomers and hydrolysis and hydrolysistotoyield yieldthe thefree, free, enantiomerically enantiomerically enriched enriched substrate. substrate. A method A method of determining of determining

optical purity optical involves making purity involves making chiral chiral esters,such esters, such as as a menthyl a menthyl ester, ester, (-)(-)menthyl e.g., e.g., menthyl chloroformatein inthethepresence chloroformate presence of of base, base, or or Mosher Mosher ester, ester, ct-methoxy-a-(trifluoromethyl)phenyl c-methoxy--(trifluoromethyl)phenyl

41

1004799942

acetate (Jacob acetate (Jacob III. III. (1982) (1982)J.J.Org. Org. Chem. Chem. 47:4165), 47:4165), of the of the racemic racemic mixture,mixture, and analyzing and analyzing the the 2023206094 18 Jul 2023

NMR spectrum NMR spectrum for presence for the the presence oftwo of the theatropisomeric two atropisomeric diastereomers. diastereomers. Stable diastereomers Stable diastereomers of of atropisomericcompounds atropisomeric compounds canseparated can be be separated and isolated and isolated by normal- by normal- and reverse-phase and reverse-phase

chromatography chromatography following following methods methods for separation for separation of atropisomeric of atropisomeric naphthyl-isoquinolines naphthyl-isoquinolines

(Hoye, T., (Hoye, T., WO 96/15111). ByBymethod WO 96/15111). method (3),a aracemic (3), racemic mixture mixture of of two two enantiomers enantiomers can can be be separated bybychromatography separated chromatographyusingusing a chiral a chiral stationary stationary phasephase (Chiral (Chiral LiquidLiquid Chromatography Chromatography

(1989) W. (1989) J. Lough, W. J. Lough,Ed. Ed. Chapman Chapmanandand Hall,NewNew Hall, York; York; Okamoto, Okamoto, (1990) (1990) J. Chromatogr. J. of of Chromatogr. 513:375-378).Enriched 513:375-378). Enriched or purified or purified enantiomers enantiomers can becan be distinguished distinguished by methods by methods used to used to distinguish other distinguish other chiral chiral molecules moleculeswith with asymmetric asymmetric carbon carbon atoms,atoms, such assuch as optical optical rotation rotation and and circular dichroism. circular dichroism.

[0191] In some

[0191] In some embodiments, embodiments, compounds compounds of the of the present present invention invention of formula of formula I (including, I (including,

but not but not limited limited toto Compound Compound 1) be 1) can cangenerally be generally prepared prepared according according to thedescribed to the method method indescribed in 2013/0123231 2013/0123231 A1, Al, the the entirety entirety of which of which is incorporated is incorporated hereinherein by reference. by reference.

[0192] some

[0192] In Insome the the embodiments, embodiments, present present invention providessynthetic inventionprovides and methods and synthetic methods synthetic intermediates synthetic intermediatesfor forthe theproduction productionof of compounds compounds of formula of formula I: I:

0 Nii N NM N CO H COH 2

O S N O 0 ' 1Ra Rª R²-O R2-0

II R or aa pharmaceutically or acceptable pharmaceutically acceptable salt salt or or agriculturally agriculturally acceptable acceptable saltsalt thereof, thereof, wherein: wherein:

Ra is Rª is an an optionally optionally substituted substitutedgroup groupselected selected from from a 3-7 a 3-7 membered membered ring having ring having 0-2 heteroatoms 0-2 heteroatoms

selected from selected fromnitrogen, nitrogen,oxygen, oxygen, andand sulfur, sulfur, andand aC1-6aliphatic; a C1-6 aliphatic;

R2 is R² is hydrogen, hydrogen, ororoptionally optionallysubstituted substitutedC1-6aliphatic; and C1-6 aliphatic; and

R 5isis hydrogen R hydrogen or or halogen. halogen. As defined

[0193] As defined

[0193] generally generally above, Rª is anRoptionally above, is an optionally substituted substituted group from group selected selected 3-7 from 3-7 membered membered ring ring andand aC1-6aliphatic. a C1-6 In some aliphatic. In some embodiments, embodiments, Rª is anRoptionally is an optionally substituted substituted 3-7 3-7 memberedring. membered ring. InInsome someembodiments, embodiments,RªRisisananoptionally optionally substituted substituted 6-membered monocyclic 6-membered monocyclic

ring. In ring. In some someembodiments, embodiments, Rª isRa anisoptionally an optionally substituted substituted 6-membered 6-membered monocyclic monocyclic

heterocyclic ring. heterocyclic ring. InInsome some embodiments, embodiments, Rª is Ra is tetrahydropyranyl. tetrahydropyranyl. In some In some embodiments, embodiments, Rª is R is tetrahydropyran-4-yl.In In tetrahydropyran-4-yl. some some embodiments, embodiments, Raoptionally Rª is an is an optionally substitutedC1-6aliphatic substituted C1-6 aliphatic group. group. In some In embodiments, some embodiments, R anisoptionally Rª is an optionally substitutedC1-6alkyl substituted group. C1-6 alkyl group.

42

1004799942

[0194] As defined

[0194] generally As defined generally above, above, R² R2 is hydrogen, is hydrogen, or optionally or optionally substitutedC1-6aliphatic. substituted C1-6 aliphatic.

In some embodiments, is hydrogen. Inembodiments, some embodiments, R 2 is optionally 18 Jul 2023

In some embodiments, R2hydrogen. R² is In some R² is optionally substitutedsubstitutedC1-6 C1-6

aliphatic. In aliphatic. In some someembodiments, embodiments, is optionally R² isR2optionally substitutedC1-6alkyl. substituted In embodiments, C1-6 alkyl. In some some embodiments, R² is C1-6alkyl. R2 is In some C1-6 alkyl. In someembodiments, embodiments, is methyl. R² isR2methyl.

[0195] As defined

[0195] As defined generally generally above above R is is hydrogen R'hydrogen or halogen. or halogen. In some In some embodiments, R is R' embodiments, is hydrogen. In hydrogen. In some some embodiments, embodiments,R R' is is halogen.InInsome halogen. some embodiments, embodiments, R'fluoro. R is is fluoro. In some

[0196] In some

[0196] embodiments, embodiments, compounds compounds of formula of formula I are prepared I are prepared according according the method the method 5 2023206094

depicted in depicted in Scheme 1, wherein Scheme 1, wherein each each ofofR, R,Re, R°,R², R2, RRare areasasdefined definedininclasses classes and and subclasses subclasses herein, both herein, singlyand both singly andinincombination. combination. Scheme1.1. Synthesis Scheme SynthesisofofCompounds Compounds of Formula of Formula I. I.

O OR ORee OR ORee N O/Br NN OI RH RH Br Br Br S S N IZ 0SO S N O ,,,O, N O N O Rª Ra H H G-2' Rªa [oxazole]

[oxazole] Oa R² O R5 G-2 R² R O O R R5 Ra Rª

G-1 G-1 S-1 S-1 G-3 G-3 S-2 S-2

0 O O N /OR° ORe N 0 N OH N S SN~OOO SS NO O O N 0 O N O ,,,O,

Rª Rª

R2 R² O2.0 0 - O R0O R2 O R² 0 - 1

Ra Rª Ra Rª

G-4 G-4 S-3 S-3 I I

[0197]

[0197] As usedherein, As used herein,RHRH a aleaving is is group. leavinggroup. In some In some embodiments, embodiments, RH is a RH is a halogen halogen or or sulfonate. In sulfonate. Insome some embodiments, is aa halogen. RHis embodiments, RH halogen. In In some some embodiments, RHisis chloro. embodiments, RH chloro. In In some some

embodiments, RH embodiments, RHisisbromo. bromo. InInsome someembodiments, embodiments, is is RH RH iodo.InIn some iodo. someembodiments, embodiments,RHRHisa is a

sulfonate. InInsome sulfonate. someembodiments, embodiments, RH isRH is a mesylate, a mesylate, a triflate, a triflate, a benenesulfonate, a benzenesulfonate, a tosylate, a tosylate, a a brosylate, or brosylate, or aa nosylate. nosylate.

[0198] As used

[0198] As used Re Re herein, herein, is is carboxylprotecting a acarboxyl In some group. In protecting group. embodiments,ReRCisis some embodiments, -Si(RP)3or -Si(RP) optionally or optionally substitutedC1-6aliphatic; substituted wherein C1-6 aliphatic; wherein eacheach RPindependently RP is is independentlyC1-6aliphatic C1-6 aliphatic

or phenyl. or phenyl. InInsome some embodiments, embodiments, Re is R° is -Si(RP)3. -Si(RP). In some In some embodiments, embodiments, R° is Re is optionally optionally substitutedC1-6aliphatic. substituted In some C1-6 aliphatic. In someembodiments, embodiments, Re isR° is optionally optionally substitutedC1-6alkyl. substituted In C1-6 alkyl. In some some embodiments, embodiments, R t-butyl. Re is is t-butyl.In In some some embodiments, embodiments, R is benzyl. Re is benzyl. In some In some embodiments, embodiments, Re is R° is benzhydryl.In Insome benzhydryl. some embodiments, embodiments, Re is R is trityl. trityl.

43

1004799942

[0199] In some

[0199] In some embodiments, embodiments, step step S-1 S-1 comprises comprises the the alkylation alkylation of of G-2byby intermediateG-2 intermediate

G-1,thereby G-3.of One 2023206094 18 Jul 2023

intermediateG-1, intermediate thereby forming forming intermediate intermediate G-3. One of ordinary ordinary skill skill will will appreciate appreciate that a that a variety of leaving variety of leaving groups groupsRHRHare suitable are suitable to to effectthethealkylation effect alkylation of of G-2. G-2. In some embodiments, In some embodiments, the alkylation the alkylation is is mediated mediatedbybya abase. base.In In some some embodiments, embodiments, theisbase the base is an alkoxide an alkoxide base. Inbase. In someembodiments, some embodiments, the base the base is anisalkali an alkali metal metal alkoxide. alkoxide. In embodiments, In some some embodiments, the the base is base is potassiumt-butoxide. potassium t-butoxide.In In some some embodiments, embodiments, theisbase the base is sodium sodium t-butoxide. t-butoxide. In some In some embodiments, embodiments, thethe base base is potassium is potassium t-amyloxide. t-amyloxide. In someInembodiments, some embodiments, the base isthe base is a a carbonate carbonate base. InInsome base. some embodiments, embodiments, the carbonate the carbonate base base is is an alkali an alkali metal metal carbonate. carbonate. In some In some embodiments, embodiments, thethe alkali alkali metal metal carbonate carbonate is potassium is potassium carbonate carbonate or cesium or cesium carbonate. carbonate. In some In some embodiments, embodiments, thethe alkali alkali metal metal carbonate carbonate is potassium is potassium carbonate, carbonate, potassium potassium bicarbonate, bicarbonate, cesium cesium carbonate, ororcesium carbonate, cesiumbicarbonate. bicarbonate. In some In some embodiments, embodiments, the metal the alkali alkalicarbonate metal carbonate is potassium is potassium

carbonate. InInsome carbonate. someembodiments, embodiments, the alkali the alkali metalmetal carbonate carbonate is potassium is potassium carbonate carbonate or potassium or potassium

bicarbonate. InInsome bicarbonate. someembodiments, embodiments, the alkali the alkali metalmetal carbonate carbonate is cesium is cesium carbonate. carbonate. In some In some embodiments, embodiments, thethe alkali alkali metal metal carbonate carbonate is cesium is cesium carbonate carbonate or cesium or cesium bicarbonate. bicarbonate. In some In some embodiments, embodiments, step step S-1S-1 proceeds proceeds in a in a polar polar solvent. solvent. In embodiments, In some some embodiments, the polar the polarissolvent solvent a is a polar aprotic polar aprotic solvent. solvent. InInsome some embodiments, embodiments, the polar the polar aprotic aprotic solvent solvent is N-methylpyrrolidone is N-methylpyrrolidone

(NMP). InInsome (NMP). someembodiments, embodiments, thethe polaraprotic polar aprotic solvent solvent is isdimethylformamide (DMF).InInsome dimethylformamide (DMF). some embodiments,the embodiments, the polar polar aprotic aproticsolvent solventis is dimethylacetamide (DMA). dimethylacetamide (DMA). In In some some embodiments, embodiments,

crystalline intermediate crystalline G-3is ispurified intermediateG-3 purifiedbybycrystallization. crystallization. In some

[0200] In some

[0200] embodiments, embodiments, S-2 S-2 step step comprises the the comprises coupling coupling of intermediateG-3G-3 of intermediate with with an an

oxazolesynthon oxazole synthon (oxazole), (oxazole), thereby thereby forming forming intermediate intermediate G-4. G-4. In some In some embodiments, embodiments, the the couplingisis aa metal-catalyzed coupling metal-catalyzedcoupling. coupling. In some In some embodiments, embodiments, the metal-catalyzed the metal-catalyzed coupling coupling is a is a Negishi coupling.OneOne Negishi coupling. of skill of skill in the in the artart willappreciate will appreciate that that a Negishi a Negishi coupling coupling is a is a transition transition

metal-catalyzedcross-coupling metal-catalyzed cross-coupling of organic of an an organic halide halide or sulfonate or sulfonate compound compound with an with an organozinc organozine

compound.InInsome compound. someembodiments, embodiments, thethe oxazole oxazole synthon synthon is isananoxazole oxazolezincate. zincate. In In some some embodiments, embodiments, thethe oxazole oxazole zincate zincate is formed is formed by metal by metal exchange exchange between between 2-lithio-oxazole 2-lithio-oxazole and a and a zinc salt. zinc salt. In someembodiments In some embodiments the zinc the zinc salt salt is ZnC2. is ZnCl. In embodiments, In some some embodiments, the the 2-lithio- 2-lithio oxazoleisis formed oxazole formedbyby treating treating oxazole oxazole withwith n-butyllithium. n-butyllithium. In embodiments, In some some embodiments, the 2-lithio the 2-lithio-

oxazoleisis formed oxazole formedat ata atemperature temperature below below -40 In -40 °C. °C.some In embodiments, some embodiments, the 2-lithio-oxazole the 2-lithio-oxazole is is formedatataatemperature formed temperature below below about about -40 In -40 °C. °C.some In some embodiments, embodiments, the 2-lithio-oxazole the 2-lithio-oxazole is is formedatataatemperature formed temperature below below -60 -60 °C. °C. In some In some embodiments, embodiments, the 2-lithio-oxazole the 2-lithio-oxazole is formed isatformed a at a temperaturebelow temperature below about about -60 -60 °C. °C. In some In some embodiments, embodiments, thecatalyst the metal metal catalyst is a palladium is a palladium

catalyst. InInsome catalyst. some embodiments, embodiments, the the palladium palladium catalyst catalystis is Pd(PPh 3) 4. In Pd(PPh). Insome some embodiments, embodiments,

crystalline intermediate crystalline G-4isispurified intermediateG-4 purifiedbybycrystallization. crystallization.

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[0201] In some

[0201] In some embodiments, embodiments, the oxazole the oxazole is treated is treated witha ametalating with metalatingagent selected from agent selected from 2023206094 18 Jul 2023

isopropyl magnesium isopropyl chloride, isopropyl magnesium chloride, isopropyl magnesium bromide, TMPZnCl-LiCl, magnesium bromide, TMPZnCl-LiCl, TMPMgCl TMPMgCl-

LiCl, and LiCl, andisopropyl isopropylmagnesium magnesium chloride/lithium chloride/lithium chloride chloride (wherein (wherein TMP TMP refers to refers to 2,2,6,6, 2,2,6,6,-

tetramethylpiperidine).InInsome tetramethylpiperidine). some embodiments, embodiments, the metalating the metalating agent agent is is isopropyl isopropyl magnesium magnesium

chloride. In chloride. In some someembodiments, embodiments, the oxazole the oxazole is treated is treated with with isopropyl isopropyl magnesium magnesium chloride chloride (2 M (2 M in THF). in Insome THF). In some embodiments, embodiments, the oxazole the oxazole is treated is treated with awith a metalating metalating agent agent at aboutat-20 about -20 °C to °C to about -10 about -10 °C. °C.InInsome some embodiments, embodiments, the oxazole the oxazole is treated is treated with awith a metalating metalating agent agent at aboutat-15 about -15 °C. In °C. In some someembodiments, embodiments, the solvent the solvent is tetrahydrofuran, is tetrahydrofuran, 2-methyltetrahydrofuran, 2-methyltetrahydrofuran, or a or a mixture mixture thereof. In thereof. someembodiments, In some embodiments, the solvent the solvent is tetrahydrofuran is tetrahydrofuran and 2-methyltetrahydrofuran. and 2-methyltetrahydrofuran. In In someembodiments, some embodiments, the reaction the reaction further further comprises comprises adding adding ZnCl toZnCl2 tooxazole form an form anzincate. oxazoleInzincate. In someembodiments, some embodiments, the reaction the reaction further further comprises comprises adding adding ZnCl asZnCl2as a solutiona solution in 2- in 2 methyltetrahydrofuran.In In methyltetrahydrofuran. some some embodiments, embodiments, the catalyst the catalyst used inused in the Negishi the Negishi couplingcoupling is a is a palladiumcatalyst palladium catalystselected selectedfrom from Pd(PPh3)4, Pd(PPh), tBuXPhos tBuXPhos Pd precatalyst, Pd precatalyst, XPhos Pd XPhos Pd precatalyst, precatalyst,

RuPhosPdPd RuPhos precatalyst, precatalyst, andand Pd-PEPPSI-IPent Pd-PEPPSI-IPent (dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol (dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-

2-ylidene](3-chloropyridyl)palladium(II)). 2-ylidene](3-chloropyridyl)palladium(Il). Such Such precatalysts precatalysts are described are described in, forin, for example, example,

Bruneauetetal., Bruneau al., ACS ACSCatal., Catal.,2015, 2015, 5(2), 5(2), pp.pp. 1386-1396. 1386-1396. In some In some embodiments, embodiments, the catalyst the catalyst is is Pd(PPh3)4. Pd(PPh). In some In some embodiments, embodiments, the reaction the reaction mixture mixture is heatedisto heated to than greater greater than about about 50 °C 50 after °C after addition of addition ofZnCl. ZnCl2.In Insome some embodiments, embodiments, the reaction the reaction mixturemixture is to is heated heated aboutto65about °C. 65 °C.

[0202] In some

[0202] In some step step embodiments, embodiments, S-3 S-3 comprises the the comprises deprotection of of deprotection esterintermediate ester G-4 intermediate G-4 to provide to provide aa compound compound of formula of formula I. InI.some In some embodiments, embodiments, where Re where Re or is benzyl is benzyl or benzhydryl, benzhydryl,

the deprotection the deprotectionisis aa catalytic catalytic hydrogenation hydrogenation using using a hydrogen a hydrogen source. source. In embodiments, In some some embodiments, the catalyst the catalyst is is aa palladium catalyst. InInsome palladium catalyst. someembodiments, embodiments, the palladium the palladium catalyst catalyst is palladium is palladium

on carbon. on In some carbon. In embodiments,the some embodiments, the hydrogen hydrogensource sourceis is H2. H. InInsome someembodiments, embodiments, residual residual

hydrogen catalyst hydrogen catalyst isisremoved removed by by means means of of aapalladium palladiumscavenger. scavenger.In Insome some embodiments, the embodiments, the

palladiumscavenger palladium scavenger is thiol. is a a thiol.In Insome some embodiments, embodiments, the is the thiol thiol is SiliaMetS SiliaMetS thiol. thiol. In someIn some embodiments, embodiments, thethe deprotection deprotection is aishydrolysis a hydrolysis reaction. reaction. In some In some embodiments, embodiments, the hydrolysis the hydrolysis is is an acidic an acidic hydrolysis. hydrolysis. InInsome some embodiments, embodiments, the is the acid acid is a strong, a strong, protic protic acid. acid. In In some some embodiments, embodiments, thethe acid acid is sulfuric is sulfuric acid.In In acid. some some embodiments, embodiments, theisacid the acid is sulfuric sulfuric acid, acid, tetrafluoroboric acid, tetrafluoroboric acid, methanesulfonic methanesulfonic acid, acid, nitricacid, nitric acid,ororhydrochloric hydrochloric acid. acid. In In some some

embodiments, embodiments, thethe reaction reaction occurs occurs in ainco-solvent, a co-solvent, wherein wherein the co-solvent the co-solvent is an alcohol. is an alcohol. In In some some embodiments, embodiments, thethe co-solvent co-solvent is 2-propanol, is 2-propanol, t-butanol, t-butanol, t-amyl t-amyl alcohol, alcohol, or ethanol. or ethanol. In In some some embodiments, embodiments, thethe co-solvent co-solvent is 2-propanol, is 2-propanol, t-butanol, t-butanol, t-amyl t-amyl alcohol, alcohol, ethanol, ethanol, or acetonitrile. or acetonitrile.

In some

[0203] In some

[0203] embodiments, embodiments, the temperature the temperature of the of the hydrolysis hydrolysis reactionisis maintained reaction maintained between5 5andand between 10 10 °C.°C. In In some some embodiments, embodiments, the temperature the temperature of the hydrolysis of the hydrolysis reaction reaction is is betweenabout between about 0 and 0 and about about 20 °C. 20 °C. In some In some embodiments, embodiments, the temperature the temperature of the hydrolysis of the hydrolysis

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1004799942

reaction is reaction is between about between about 2 and 2 and about about 8 °C. 8 °C. In some In some embodiments, embodiments, the temperature the temperature of the of the hydrolysisreaction reactionisis maintained maintainedbetween between about 2 and2 about and about 10 °C. 10 In °C. some In some embodiments, the 18 Jul 2023

hydrolysis about embodiments, the

productisis purified product purified by bycrystallization. crystallization. InInsome some embodiments, embodiments, the product the product is crystallized is crystallized from from an an alcohol solution. alcohol solution. InInsome some embodiments, embodiments, the alcohol the alcohol solution solution is a mixture is a mixture of ethanol of ethanol and and water. water. In some In embodiments, some embodiments, the product the product is crystallized is crystallized from from a mixture a mixture of acetonitrile of acetonitrile and and water. water.

[0204]

[0204] In embodiments, someembodiments, In some intermediates intermediates of formula G-1 areG-1 of formula prepared accordingaccording are prepared to the to the methoddepicted method depicted in in Scheme Scheme 2, wherein 2, wherein each each of ofR, R, RH, R²,RH, R2as R are , R'defined are as indefined classesinand classes and 2023206094

subclasses herein, subclasses herein,both bothsingly singlyandand in in combination. combination.

Scheme2.2. Synthesis Scheme SynthesisofofIntermediates IntermediatesofofFormula FormulaG-1G-1

OH OH RH RH .,'Ra O Rª .,O' O Ra R 0*0R Rª R2 O R² 0 NR2 R² o

R5 R5 G-5 R S-4 S-4 G-1 G-1 R G-5

[0205]

[0205] In someembodiments, In some embodiments,step step S-4 comprises S-4 comprises the conversion the conversion of the hydroxyl of the hydroxyl group of group of

intermediateG-5 intermediate G-5to toa aleaving leaving group, group, RH.RH. In some In some embodiments, embodiments, intermediate intermediate G-5 is anG-5 is an alcohol alcohol or an or oxygenanion an oxygen anion thereof.In some thereof. In some embodiments, embodiments, where where RH RH is a sulfonate is a sulfonate group, group, G-5 G-5 is is treated treated with aa sulfonylating with sulfonylatingreagent. reagent.InInsome some embodiments, embodiments, the sulfonate the sulfonate group group is is a mesylate, a mesylate, a triflate, a triflate,

a benzenesulfonate, a a tosylate,a abrosylate, benzenesulfonate, a tosylate, brosylate,orora anosylate. nosylate.In In some some embodiments, embodiments, the the sulfonylating reagent sulfonylating reagentisisa asulfonyl sulfonylhalide. halide.InInsome some embodiments embodiments the sulfonylating the sulfonylating reagent reagent is a is a sulfonyl chloride. sulfonyl chloride. In In some someembodiments embodiments the sulfonyl the sulfonyl chloride chloride is methanesulfonyl is methanesulfonyl chloride.chloride.

[0206]

[0206] In someembodiments, In some wherewhere embodiments, RH is RH is a halogen, a halogen, the hydroxyl group isgroup the hydroxyl is converted converted

directly to directly to aa halogen bymeans halogen by meansof of a halogenating a halogenating reagent. reagent. In some In some embodiments, embodiments, the the halogenatingreagent halogenating reagent is is a a brominating brominating reagent. reagent.

[0207]

[0207] In embodiments, someembodiments, In some wherewhere RH is RH is a halogen, a halogen, the hydroxyl the hydroxyl first is group isgroup first converted converted

to aa first to firstleaving leaving group, group, and then that and then that first first leaving leaving group is further group is further converted convertedtotothe thehalogen. halogen.In In someembodiments, some embodiments, the first the first leaving leaving group group is a is a sulfonate. sulfonate. In some In some embodiments, embodiments, the sulfonate the sulfonate is is a mesylate, a mesylate, aatriflate, triflate, aabenzenesulfonate, benzenesulfonate, a atosylate, tosylate, aa brosylate, brosylate, or or aa nosylate. nosylate. InInsome some embodiments, embodiments, thethe sulfonate sulfonate is ais methanesulfonate. a methanesulfonate. In embodiments, In some some embodiments, the the methanesulfonylate methanesulfonylate is is formed formed by treatment by treatment ofwith of G-5 G-5 methanesulfonyl with methanesulfonyl chloride.chloride. In some In some embodiments, embodiments, thethe sulfonate sulfonate is formed is formed in the in the presence presence of a of a base. base. In embodiments, In some some embodiments, the base the base is an is an amine base.InInsome amine base. some embodiments, embodiments, the amine the amine base isbase is triethylamine, triethylamine, diisopropylethylamine diisopropylethylamine

(Hunig'sbase), (Hunig's base),1,8-diazabicyclo[5.4.0]undec-7-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, pyridine, or dimethylaminopyridine or dimethylaminopyridine

(DMAP).InInsome (DMAP). someembodiments, embodiments, thethe amine amine base base is istrimethylamine. trimethylamine. In In some someembodiments, embodiments,the the aminebase amine baseisistriethylamine. triethylamine.In In some some embodiments, embodiments, the solvent the solvent is 2-methyltetrahydrofuran, is 2-methyltetrahydrofuran,

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1004799942

tetrahydrofuran, orordichloromethane. tetrahydrofuran, dichloromethane. In some In some embodiments, embodiments, the solvent the solvent is 2- is 2 2023206094 18 Jul 2023

methyltetrahydrofuran.In In methyltetrahydrofuran. some some embodiments, embodiments, the reaction the reaction furtherfurther comprises comprises a promoter. a promoter. In In some embodiments, some embodiments,the thepromoter promoterisis Nal Nal or or tetrabutylammonium iodide. In tetrabutylammonium iodide. In some embodiments, some embodiments,

the reaction the takes place reaction takes place atat about about2020°C°Ctotoabout about 30 30 °C.°C. In In some some embodiments, embodiments, the reaction the reaction takes takes place at place at about 22°C. about22 °C.

[0208] In some

[0208] In some embodiments, embodiments, the first the first group leaving leaving is group furtherisconverted further converted to by to a halogen a halogen by displacement with displacement with halide. halide. In Insome some embodiments, the halide embodiments, the halide isisbromide. bromide.InInsome someembodiments, embodiments,

the source the source ofofhalide halideisis aa metal metalhalide. halide. InInsome some embodiments, embodiments, the source the source of bromide of bromide is a is a metal metal bromide.In Insome bromide. some embodiments, embodiments, the bromide the metal metal bromide is anmetal is an alkali alkalibromide. metal bromide. In some In some embodiments, embodiments, thethe alkali alkali metal metal bromide bromide is LiBr. is LiBr. In embodiments, In some some embodiments, the alkalithe alkali metal metal bromide bromide is NaBr. is NaBr. InInsome some embodiments, embodiments, the alkali the alkali metalmetal bromide bromide is KBr. isInKBr. some In some embodiments, embodiments, this this displacementfurther displacement furthercomprises comprises a promoter. a promoter. In some In some embodiments, embodiments, the promoter the promoter is a phaseis a phase transfer catalyst. transfer catalyst. The promotercancan The promoter include, include, butbut is is notnot limited limited to to tetramethylammonium tetramethylammonium bromide bromide

or tetrabutylammonium or bromide. tetrabutylammonium bromide. In embodiments, In some some embodiments, the displacement the displacement takes place takes place in a polar in a polar solvent. InInsome solvent. someembodiments, embodiments, the polar the polar solvent solvent is a polar is a polar aprotic aprotic solvent. solvent. In In some some embodiments, the embodiments, the polar polar aprotic aproticsolvent solventis is N-methylpyrrolidone (NMP). N-methylpyrrolidone (NMP).InInsome someembodiments, embodiments,

the polar the aprotic solvent polar aprotic solventisis dimethylformamide dimethylformamide (DMF). (DMF). Inembodiments, In some some embodiments, the polar the polar aprotic aprotic solvent is solvent is dimethylacetamide dimethylacetamide (DMAc). (DMAc). In embodiments, In some some embodiments, the polar the polarsolvent aprotic aproticissolvent ethyl is ethyl acetate (EtOAc). acetate (EtOAc).InInsome some embodiments, embodiments, the reaction the reaction takes at takes place place at 50 about about 50about °C to °C to60about °C. 60 °C. In some In embodiments, some embodiments, the reaction the reaction takestakes placeplace at about at about 55 °C.55In°C. In embodiments, some some embodiments, leaving leaving groupformation group formationstep stepS-4S-4 andand alkylation alkylation stepstep S-1 S-1 are performed are performed together together withoutwithout the isolation the isolation of of G-1. intermediateG-1. intermediate

[0209] In some

[0209] In some embodiments, embodiments, intermediates intermediates of formula of formula G-5 are are prepared G-5prepared according to theto according the method depicted method depictedininScheme Scheme 3, wherein 3, wherein each each of R,ofR², Ra,R R 2 are R 5 defined , as are as defined in and in classes classes and subclasses herein, subclasses herein,both bothsingly singlyandand in in combination. combination.

Scheme3.3. Synthesis Scheme SynthesisofofIntermediates IntermediatesofofFormula FormulaG-5G-5

CHO o OH OH CHO 0 Ra-OH 0 R-OH O Ra Rª R²

R0R 5 R² R O : R20o R²

R R R G-6 G-6 S-5 S-5 rac-G-7 rac-G-7 S-6 S-6 rac-G-5 rac-G-5

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1004799942

[acyl]

[acyl]

OH OH 'O OH OH 2023206094 18 Jul 2023

o O o Rª

[acyl] donor

[acyl] donor O'Ra Rª O Rª Ra Ra R + + R00 I R20 O R² O R² O R²

1! R 5 R5 R5 R R R S-7 S-7 (S)-G-5 (S)-G-5 (R)-G-8 (R)-G-8 S-8 S-8 (R)-G-5 (R)-G-5

[0210] In some

[0210] In some embodiments, embodiments, step step S-5 S-5 comprises comprises the the epoxidation epoxidation of aldehyde of aldehyde G-6, thereby G-6, thereby formingthe forming theepoxide epoxideof of formula formula rac-G-7. rac-G-7. In embodiments, In some some embodiments, the epoxidation the epoxidation is a Corey-is a Corey Chaykovsky Chaykovsky epoxidation. epoxidation. One One of of in skill skill theinart thewill art will appreciate appreciate that athat a Corey-Chaykovsky Corey-Chaykovsky

epoxidationisisthe epoxidation theuse useofofaasulfur sulfurylide ylidetoto convert converta acarbonyl carbonyl compound compound to itstocorresponding its corresponding epoxide. InInsome epoxide. some embodiments, embodiments, the sulfur the sulfur ylide ylide is formed is formed from a from a trimethylsulfonium trimethylsulfonium or or trimethylsulfoxonium trimethylsulfoxonium salt. salt. In In some some embodiments, embodiments, the sulfur the sulfur ylide ylide is is formed formed from from trimethylsulfoxonium trimethylsulfoxonium iodide. iodide. In some In some embodiments, embodiments, the ylide the sulfur sulfurisylide is formed formed from from trimethylsulfoxonium trimethylsulfoxonium mesylate. mesylate.

[0211] In some

[0211] In some embodiments, S-6 S-6 step step embodiments, comprises comprises epoxide epoxide opening opening of intermediate of intermediate rac-G-7 rac-G-7

by an alcohol by an alcoholofofformula formula Ra-OH, R-OH, wherein wherein R defined Rª is as is as defined in classes in classes and subclasses and subclasses herein, herein,

thereby forming thereby forming intermediate intermediate rac-G-5. rac-G-5. In embodiments, In some some embodiments, theopening the epoxide epoxideis opening acid is acid catalyzed. InInsome catalyzed. some embodiments, embodiments, the is the acid acid is a Lewis a Lewis acid. acid. In someInembodiments, some embodiments, the Lewis the Lewis acid is acid is aa metal halide or metal halide or metal metalsulfonate. sulfonate. InInsome some embodiments, embodiments, the Lewis the Lewis acid isacid is ansalt. an iron iron salt. In some In embodiments,the some embodiments, the Lewis Lewisacid acid is is FeCl3. In some FeCl. In some embodiments, embodiments,step stepS-6 S-6 is is conducted conducted

withoutadditional without additionalsolvent. solvent.InInsome some embodiments, embodiments, the Lewis the Lewis acid isacid is BF BF-EtO. In3 -Et2O. some In some embodiments, embodiments, thethe solvent solvent of step of step S-6 S-6 is toluene. is toluene. In some In some embodiments, embodiments, the acidthe is acid is HBF4-OEt2, HBF4-OEt2,

HBF4-water, HBF4-water, or or camphorsulfonic camphorsulfonic acid. acid. In some In some embodiments, embodiments, theofsolvent the solvent step S-6 step of is S-6 is dichloromethane. dichloromethane.

[0212] In some

[0212] In some embodiments, S-7 S-7 step step embodiments, comprises the the comprises selective selective acylation the (R)-isomer acylationofofthe of (R)-isomer of intermediateG-5, intermediate G-5,with with an an [acyl]

[acyl] donor, donor, thereby thereby producing producing intermediate intermediate (R)-G-8(R)-G-8 and and residual residual (S)-G-5. InInsome (S)-G-5. some embodiments, embodiments, the [acyl] the [acyl] donor donor is of is of the the formula formula RIC(O)OR, R*C(O)ORY, wherein RX wherein is R is optionally substituted optionally substitutedC-4 aliphatic;and C1-4aliphatic; andRYRY is is optionally optionally substituted substituted C1-4 C1-4 aliphatic aliphatic or or optionally optionally

substituted C1-4 acyl. substituted C1-4 acyl. In In some someembodiments, embodiments, the [acyl] the [acyl] donordonor provides provides a C4-acyl a C4-acyl group. group. In some In some embodiments, embodiments, thethe [acyl]

[acyl] donor donor is optionally is an an optionally substituted substituted 4-7 membered 4-7 membered lactone lactone or an or an optionally substituted optionally substituted4-7 4-7membered membered cyclic cyclic anhydride. anhydride. Inembodiments, In some some embodiments, the [acyl]the [acyl] donor donor is an is an optionally substituted 4-7 optionally substituted 4-7 membered membered cyclic cyclic anhydride. anhydride. In embodiments, In some some embodiments, the [acyl]the [acyl] donorisis vinyl donor vinyl acetate, acetate, and and[acyl]

[acyl]isis acetyl. acetyl. In In some some embodiments, embodiments, the [acyl] the [acyl] donordonor is vinyl is vinyl

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1004799942

butyrate, and butyrate, and[acyl]

[acyl] isis butyryl. butyryl. InInsome some embodiments, embodiments, the [acyl] the [acyl] donordonor is succinic is succinic anhydride, anhydride, 2023206094 18 Jul 2023

and [acyl] and [acyl] is is succinyl. succinyl.

[0213] In some

[0213] In some embodiments, embodiments, the acylation a kineticresolution. is ais kinetic the acylation In some resolution. In embodiments some embodiments

the kinetic the resolution is kinetic resolution is accomplished accomplished by by a lipase a lipase enzyme. enzyme. In some In some embodiments, embodiments, the the lipase lipase enzymeis isCandida enzyme Candida antarctica antarctica lipase lipase B (CAL-B). B (CAL-B). Inembodiments, In some some embodiments, the lipasethe lipase enzyme is enzyme is Novozyme 435.435. Novozyme In some In some embodiments, embodiments, the acylation the acylation reaction reaction is conducted is conducted in THF in THF solvent. In solvent. In

someembodiments, some embodiments, the acylation the acylation reaction reaction is conducted is conducted in toluene in toluene solvent. solvent. In someIn some embodiments, embodiments, thethe acylation acylation reaction reaction is conducted is conducted in a in a mixture mixture of THFof THF and and toluene. toluene. In some In some embodiments, embodiments, when when [acyl]

[acyl] is succinyl, is succinyl, unreacted unreacted intermediate intermediate G-5 is G-5 is separated separated from by from (R)-G-8 (R)-G-8 by formingthe forming thesuccinate succinateanion anion under under aqueous aqueous basicbasic conditions conditions and extracting and extracting the unreacted the unreacted neutral neutral alcohol species alcohol speciesinto intoananorganic organicsolvent. solvent.

[0214] In some

[0214] In some embodiments, embodiments, step step S-8 S-8 comprises comprises the the hydrolysis hydrolysis of of enantiomerically enantiomerically

enrichedintermediate enriched intermediate(R)-G-8, (R)-G-8, thereby thereby forming forming (R)-G-5. (R)-G-5. In some In some embodiments, embodiments, the the hydrolysis hydrolysis is an is an aqueous hydrolysis.In In aqueous hydrolysis. some some embodiments, embodiments, the aqueous the aqueous hydrolysis hydrolysis is an is an alkaline alkaline hydrolysis. InInsome hydrolysis. some embodiments, embodiments, the aqueous the aqueous hydrolysis hydrolysis is mediated is mediated by hydroxide. by hydroxide. In some In some embodiments, the embodiments, the aqueous aqueous hydrolysis hydrolysis is is mediated mediated by by sodium sodium hydroxide. In some hydroxide. In embodiments, some embodiments,

steps S-7 steps S-7 and andS-8 S-8are areperformed performed without without the isolation the isolation of intermediate of intermediate (R)-G-8. (R)-G-8.

In some

[0215] In some

[0215] embodiments, embodiments, the (R)-G-8 the (R)-G-8 produced produced has an an enantiomeric hasenantiomeric excess excess of greater of greater

than 70%, than 80%, 90%, 70%, 80%, 95%,97%, 90%,95%, 97%, 98%, 98%, 99%, 99%, or 99.5%. or 99.5%.

[0216] In some

[0216] In some embodiments, embodiments, compounds compounds of formula of formula G-4 are are prepared G-4prepared according according to to the the methoddepicted method depicted in in Scheme Scheme 4, wherein 4, wherein each each of of R, R, Re, RH,R, R²,RH, R2as R are 5 , Rdefined are as indefined classesinand classes and subclasses herein, subclasses herein,both bothsingly singlyandand in in combination. combination.

Scheme4.4. Alternate Scheme AlternateSynthesis SynthesisofofIntermediates IntermediatesofofFormula FormulaG-4G-4

00 O O ORe ORe N N ORe N N RH RH ON ,,,0, 01aC0 O S S IZ O0 N -- O 0 O S NO O N Rª O ."0H ,,,0, 'Ra R²·O G-9 Rª 0 R2. G-9 Ra R² O RI Z R5 R R Rª

G-1 G-1 S-9 S-9 G-4 G-4

[0217]

[0217] In someembodiments, In some embodiments,step step S-9 comprises S-9 comprises the alkylation the alkylation of intermediate of intermediate G-9 by alkyl G-9 by alkyl

halide G-1, halide G-1, thereby therebyforming forming intermediate G-4. G-4. intermediate In embodiments, In some some embodiments, the alkylation the alkylation is is mediated mediated by by aa base. base. InInsome some embodiments, embodiments, the is the base base an is an alkoxide alkoxide base. base. In someIn some embodiments, embodiments, the base the base is an is an alkali alkali metal alkoxide. InInsome metal alkoxide. some embodiments, embodiments, the is the base base is potassium potassium t-butoxide. t-butoxide. In some In some embodiments, embodiments, thethe base base is sodium is sodium t-butoxide. t-butoxide. In embodiments, In some some embodiments, thepotassium the base is base is potassium t- t

49

1004799942

amyloxide. In amyloxide. In some someembodiments, embodiments,the thebase baseisis aa carbonate carbonate base. base. In Insome some embodiments, the embodiments, the 2023206094 18 Jul 2023

carbonatebase carbonate baseisisananalkali alkali metal metalcarbonate. carbonate.In In some some embodiments, embodiments, the metal the alkali alkali carbonate metal carbonate is is sodiumcarbonate, sodium carbonate,sodium sodium bicarbonate, bicarbonate, potassium potassium carbonate, carbonate, potassium potassium bicarbonate, bicarbonate, cesium cesium carbonate, cesium carbonate, cesium bicarbonate, bicarbonate, potassium potassium phosphate phosphate tribasic, tribasic, or potassium or potassium phosphate phosphate dibasic. dibasic. In In someembodiments, some embodiments, the alkali the alkali metal metal carbonate carbonate is potassium is potassium carbonate carbonate or carbonate. or cesium cesium carbonate. In In someembodiments, some embodiments, the alkali the alkali metal metal carbonate carbonate is potassium is potassium carbonate. carbonate. In some In some embodiments, embodiments,

the alkali the alkali metal carbonateisispotassium metal carbonate potassium bicarbonate. bicarbonate. In some In some embodiments, embodiments, the metal the alkali alkali metal carbonateisis cesium carbonate cesiumbicarbonate. bicarbonate. In In some some embodiments, embodiments, step step S-9 S-9 proceeds proceeds in solvent. in a polar a polar solvent. In In someembodiments, some embodiments, the polar the polar solvent solvent is a is a polar polar aprotic aprotic solvent. solvent. In embodiments, In some some embodiments, the polar the polar aprotic solvent aprotic solvent isis N-methylpyrrolidone (NMP). N-methylpyrrolidone (NMP). In someInembodiments, some embodiments, the polar the polar aprotic aprotic solvent solvent is dimethylformamide is (DMF). dimethylformamide (DMF). Inembodiments, In some some embodiments, the polar the polar aprotic aprotic solvent is solvent is dimethylacetamide dimethylacetamide (DMA). (DMA). In embodiments, In some some embodiments, the takes the reaction reaction takes place at a place at a temperature temperature of of about 9090°C°Ctotoabout about about100100 °C.°C. In In some some embodiments, embodiments, the reaction the reaction takesatplace takes place at a temperature a temperature of of about 100 about 100°C°Ctotoabout about 140140 °C. °C. In some In some embodiments, embodiments, the reaction the reaction takesatplace takes place at a temperature a temperature of of about 115 about 115°C. °C.

[0218] In some

[0218] In some embodiments, embodiments, compounds compounds of formula of formula G-2G-9and G-2 and G-9 are are prepared prepared according according to to the method the depicted method depicted in in Scheme Scheme 5, wherein 5, wherein Re is Re as is as defined defined in classes in classes and subclasses and subclasses herein.herein.

Scheme5.5. Synthesis Scheme SynthesisofofIntermediates IntermediatesofofFormulas Formulas G-2 G-2 andand G-9 G-9

CO2 Et COEt O2Et COEt + H2 N O R Re -NH O + HN NH O Re R S S NH 2 Ó S NH O O N IZ N H H G-10 G-10 G-11 G-11 S-10 S-10 G-12 G-12 CO 2 Et COEt 0 O O, O O. S Re Br Br NO S 0 NH O'Re Re Br Br N O0 'R S O IZ N N O O H H H S-11 S-11 G-13 G-13 S-12 S-12 G-2 G-2 0 O O, 0N SR N N Re

O S N O H O H S-13 S-13 G-9 G-9

[0219]

[0219] In In some embodiments, someembodiments, S-10 S-10 step step comprises a urea aformation comprises between between urea formation intermediates intermediates

G-10(or G-10 (ora asalt salt thereof), thereof), and andG-11 G-11(or(ora salt a saltthereof), thereof),thereby therebyforming forming the the intermediate intermediate of of 50

1004799942

formulaG-12. formula G-12.In In some some embodiments, embodiments, theformation the urea urea formation proceed proceed using using asource. a carbonyl carbonyl In source. In 2023206094 18 Jul 2023

some embodiments, some embodiments,the thecarbonyl carbonyl source source is is carbonyldiimidazole carbonyldiimidazole (CDI). (CDI). In In some embodiments, some embodiments,

the carbonyl the carbonylsource sourceisistriphosgene. triphosgene.In In some some embodiments, embodiments, the intermediate the intermediate ofG-11 of formula formula is G-11 is used as used as its its hydrochloride salt. InInsome hydrochloride salt. some embodiments, embodiments, an additional an additional base base is is used. used. In someIn some embodiments, embodiments, thethe base base is an is an amine amine base.base. In some In some embodiments, embodiments, the amine the amine base base is triethylamine. is triethylamine.

In some

[0220] In some

[0220] step step embodiments, embodiments, S-11S-11 comprises comprises the bromination the bromination of an of of an intermediate of intermediate formula G-12, formula thereby forming G-12, thereby an intermediate forming an intermediate of offormula formulaG-13. G-13. In In some some embodiments, the embodiments, the

brominating reagent brominating reagent isisN-bromosuccinimide. In some N-bromosuccinimide. In some embodiments, embodiments,the thebromination brominationisis conductedinina apolar conducted polaraprotic aproticsolvent. solvent.In In some some embodiments, embodiments, the aprotic the polar polar aprotic solventsolvent is is dimethylformamide(DMF). dimethylformamide (DMF). In some

[0221] In some

[0221] embodiments, S-12S-12 step step embodiments, comprises comprises the intramolecular the intramolecular cyclizationofofanan cyclization

intermediateofofformula intermediate formula G-13, G-13, thereby thereby forming forming an intermediate an intermediate of formula of formula G-2. In G-2. some In some embodiments, embodiments, thethe intramolecular intramolecular cyclization cyclization is effected is effected by a by a strong strong base.base. Inembodiments, In some some embodiments, the strong the strong base baseisis an an alkali alkali metal metal alkoxide. alkoxide.InInsome some embodiments, embodiments, the alkali the alkali metal metal alkoxide alkoxide is is potassiumt-butoxide. potassium t-butoxide.In In some some embodiments, embodiments, the intramolecular the intramolecular cyclization cyclization is conducted is conducted in an in an ether solvent. ether solvent. InInsome some embodiments, embodiments, the ether the ether solvent solvent is 1,4-dioxane. is 1,4-dioxane.

[0222] In some

[0222] In some embodiments, S-13S-13 step step embodiments, comprises comprises the coupling the coupling of intermediate of intermediate G-2 G-2 with an an with oxazolesynthon oxazole synthon (oxazole (oxazole or oxazole or oxazole metallate), metallate), thereby thereby forming forming intermediate intermediate G-9. In G-9. some In some embodiments, embodiments, thethe coupling coupling is aismetal-catalyzed a metal-catalyzed coupling. coupling. In someInembodiments, some embodiments, the metal- the metal catalyzed coupling catalyzed couplingisisa aNegishi Negishicoupling. coupling. One One of skill of skill in the in the art art willwill appreciate appreciate thatthat a Negishi a Negishi

couplingisis aa transition coupling transition metal-catalyzed metal-catalyzedcross-coupling cross-coupling of organic of an an organic halide halide or sulfonate or sulfonate

compoundwith compound withananorganozine organozinccompound. compound.In In some some embodiments, embodiments, the the oxazole oxazole synthon synthon is an is an

oxazolezincate. oxazole zincate.InInsome some embodiments, embodiments, the oxazole the oxazole zincatezincate is formed is formed by metalby metal exchange exchange between2-lithio-oxazole between 2-lithio-oxazole andand a zinc a zinc salt.In In salt. some some embodiments embodiments the zincthe zinc salt is salt is In ZnCl. ZnCl2. some In some embodiments, embodiments, thethe 2-lithio-oxazole 2-lithio-oxazole is formed is formed by treating by treating oxazole oxazole with n-butyllithium. with n-butyllithium. In some In some embodiments, embodiments, thethe 2-lithio-oxazole 2-lithio-oxazole is formed is formed at a at a temperature temperature below below -40 °C.-40 °C. In some In some embodiments, embodiments, thethe 2-lithio-oxazole 2-lithio-oxazole is formed is formed at a at a temperature temperature below below -60 °C.-60 °C. In some In some embodiments, embodiments, thethe transition transition metal metal catalyst catalyst is ais palladium a palladium catalyst. catalyst. In some In some embodiments, embodiments, the the palladiumcatalyst palladium catalystisisPd(PPh). Pd(PPh3)4. In some In some embodiments, embodiments, crystalline crystalline intermediate intermediate G-4 is G-4 is purified purified by crystallization. by crystallization. In some

[0223] In some

[0223] embodiments, embodiments, the oxazole the oxazole is treated witha ametalating is treatedwith metalating agent selected from agent selected from

isopropyl magnesium isopropyl chloride, isopropyl magnesium chloride, isopropyl magnesium bromide, TMPZnCl-LiCl, magnesium bromide, TMPZnCl-LiCl, TMPMgCl TMPMgCl-

LiCl, and LiCl, and isopropyl isopropylmagnesium magnesium chloride/lithium chloride/lithium chloride chloride (wherein (wherein TMP TMP refers to refers to 2,2,6,6, 2,2,6,6,-

tetramethylpiperidine).InInsome tetramethylpiperidine). some embodiments, embodiments, the metalating the metalating agent agent is is isopropyl isopropyl magnesium magnesium

chloride. In chloride. In some someembodiments, embodiments, the oxazole the oxazole is treated is treated with with isopropyl isopropyl magnesium magnesium chloride chloride (2 M (2 M

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in THF). in Insome THF). In some embodiments, embodiments, the oxazole the oxazole is treated is treated with awith a metalating metalating agent agent at aboutat-20 about -20 °C to °C to 2023206094 18 Jul 2023

about -10 about -10 °C. °C.InInsome some embodiments, embodiments, the oxazole the oxazole is treated is treated with awith a metalating metalating agent agent at aboutat about -15 °C. -15 °C. In In some someembodiments, embodiments, the solvent the solvent is tetrahydrofuran, is tetrahydrofuran, 2-methyltetrahydrofuran, 2-methyltetrahydrofuran, or a or a mixturethereof. mixture thereof.InInsome some embodiments, embodiments, the solvent the solvent is tetrahydrofuran is tetrahydrofuran and 2- and 2 methyltetrahydrofuran.In In methyltetrahydrofuran. some some embodiments, embodiments, the reaction the reaction furtherfurther comprises comprises adding adding ZnCl to ZnCl2 to formananoxazole form oxazolezincate. zincate.In In some some embodiments, embodiments, the reaction the reaction furtherfurther comprises comprises adding adding ZnCl as aZnCl2as a solution in solution in 2-methyltetrahydrofuran. 2-methyltetrahydrofuran. In In some some embodiments, embodiments, the catalyst the catalyst used inused in the Negishi the Negishi

couplingisis aa palladium coupling palladiumcatalyst catalystselected selectedfrom from Pd(PPh3)4, Pd(PPh), tBuXPhos tBuXPhos Pd precatalyst, Pd precatalyst, XPhos Pd XPhos Pd precatalyst, RuPhos precatalyst, RuPhosPdPd precatalyst, precatalyst, andand Pd-PEPPSI-IPent Pd-PEPPSI-IPent (dichloro[1,3-bis(2,6-di-3 (dichloro[1,3-bis(2,6-di-3-

pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)). pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(I). Such precatalysts Such precatalysts are are describedin, described in, for for example, example,Bruneau Bruneau et al.,ACSACS et al., Catal., Catal., 2015, 2015, 5(2),5(2), pp. 1386-1396. pp. 1386-1396. In someIn some embodiments, embodiments, thethe catalyst catalyst is is Pd(PPh3)4. Pd(PPh). In embodiments, In some some embodiments, the mixture the reaction reactionismixture is heated to heated to greater than greater than about about5050°C°Cafter afteraddition additionof of ZnC2. ZnCl. In some In some embodiments, embodiments, the reaction the reaction mixture mixture is is heated toto about heated about6565°C. °C. Scheme6.6. Synthesis Scheme SynthesisofofIntermediate IntermediateG-13-a G-13-a CO 2 Et CO 2 Et COEt COEt Oo O. O O 0 S NH 'Re Re - CI CI s NH NH O 'RRe S NH S O N O0 N IZ N O N H O H H H G-12 G-12 G-13-a G-13-a

[0224]

[0224] In embodiments, someembodiments, In some S-11 S-11 step step comprises comprises the chlorination the chlorination of an intermediate of an intermediate of of formula G-12, formula thereby forming G-12, thereby an intermediate forming an intermediate of offormula formulaG-13-a. G-13-a. In Insome some embodiments, the embodiments, the

chlorinating reagent chlorinating reagentisis N-chlorosuccinimide. N-chlorosuccinimide. In some In some embodiments, embodiments, G-13-a G-13-a can be usedcan in be used step in step S-12 inin place S-12 place ofofG-13 G-13as asdescribed described above above to form to form the chloro the chloro analoganalog of G-2,ofwhich G-2, can which can in be used be used in step S-13 step S-13 inin place place ofofG-2. G-2.

[0225] SomeSome

[0225] embodiments embodiments provide for a for provide a process process for preparing for preparing Compound Compound 1: 1: 0 o N OH N S o O N O O 0 0 O O

Compound 11 Compound comprising contacting comprising contacting compound G-4-a: compound G-4-a:

52

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0 2023206094 18 Jul 2023

N N Os O S NO S N *0 O O 0 O

G-4-a G-4-a

with acid. with acid.

[0226] SomeSome

[0226] embodiments embodiments provide for a for provide a process process for preparing for preparing compound compound G-4-a: G-4-a:

0 O N N NN "O O S N bN 0

G-4-a G-4-a

comprising contacting comprising contacting compound G-9-a: compound G-9-a:

0 O N N S O O N O H H G-9-a G-9-a with aa compound with ofthe compound of the formula formula H-1: H-1:

RH o O o

H-1 H-1 whereinRHRH wherein is ishalogen. halogen.

[0227] In some

[0227] In some embodiments, embodiments, RH isRH is bromo. bromo.

[0228] SomeSome

[0228] embodiments embodiments provide for a for provide a process process for preparing for preparing Compound Compound 1: 1:

53

1004799942

2023206094 18 Jul 2023 N OH OH N N O S N O O o O 0 O O

Compound 11 Compound comprising contacting comprising contacting aa compound of the compound of the formula formula G-4-b: G-4-b:

~NN /~ N N 0 O S S N- O ,Oo N

O O 1 O

G-4-b G-4-b

with aa hydrogen with hydrogen source source andand a palladium a palladium catalyst. catalyst.

[0229] SomeSome

[0229] embodiments embodiments provide for a for provide a process process for preparing for preparing an enantiomerically an enantiomerically enriched enriched

compoundofofformula compound formula(R)-G-5: (R)-G-5: OH OH .,O Rª Ra R2. R² R

(R)-G-5 (R)-G-5 R whereinRªRisisananoptionally wherein optionallysubstituted substitutedgroup group selected selected fromfrom a 3-7a membered 3-7 membered ring 0-2 ring having having 0-2 heteroatomsselected heteroatoms selected from from nitrogen, nitrogen, oxygen, oxygen, and sulfur, and sulfur, and aliphatic; and C1-6 C1-6 aliphatic;

R2 is R² is hydrogen, hydrogen, ororoptionally optionallysubstituted substituted C1-6 aliphatic;and aliphatic; C1-6 and R 5isis hydrogen R hydrogen or or halogen; comprisingthe comprising thesteps stepsof:of: a) contacting a) contacting aa racemic racemic compound compound ofofformula rac-G-5: formularac-G-5: OH OH 0 o 'Ra Rª R20 R²·O

1 R5 rac-G-5 rac-G-5 R with aa lipase with lipase enzyme enzyme andand an an [acyl]

[acyl] donor, donor, thereby thereby forming forming a compound a compound of(R)-G-8: of formula formula (R)-G-8:

54

1004799942

[acyl]'

[acyl] 0 O 2023206094 18 Jul 2023

.O ,'Ra Rª

R²R20 o

(R)-G-8 (R)-G-8 R wherein [acyl]isis aaC1-C7 wherein[acyl] acylgroup; Ci-C7acyl group; andand

b) removing removingthe the [acyl]

[acyl] group; group;

thereby preparing thereby preparingthe theenantiomerically enantiomerically enriched enriched compound compound of formula of formula (R)-G-5. (R)-G-5.

In some

[0230] In some

[0230] embodiments, embodiments, the compound the compound of formula of formula (R)-G-5 (R)-G-5 is: is: OH OH O O

(R)-G-5. (R)-G-5.

[0231]

[0231] In In some embodiments, someembodiments, the [acyl] the [acyl] donor donor an optionally is anisoptionally substituted substituted 4-7 membered 4-7 membered

lactone or lactone or 4-7 4-7 membered membered optionally optionally substituted substituted cyclic cyclic anhydride; anhydride; or a compound or a compound of the of the formula formula RxC(O)ORY, R*C(O)ORV, wherein wherein Rx isRx is optionally optionally substituted substituted C1-4 aliphatic; C1-4 aliphatic; and and RY is RY is optionally optionally substituted substituted

C1-4 aliphatic C1-4 aliphatic or or optionally substituted C1-4 optionally substituted acyl. C1-4 acyl.

[0232]

[0232] In someembodiments, In some embodiments, the [acyl] the [acyl] is a isC aacyl C4 acyl group. group.

[0233]

[0233] In In some embodiments, someembodiments, the lipase the lipase enzyme enzyme is Candida is Candida antarctica antarctica lipase B. lipase B.

[0234]

[0234] embodiments Someembodiments Some provide provide fora aprocess for process of preparing aa compound of preparing G-9-a: compound G-9-a:

0 O N N N O N S IZ O O N H H G-9-a G-9-a contacting compound contacting G-2-a: compound G-2-a:

0 O Br Br 0 N N S S N- OO IZ N H O H G-2-a G-2-a

with oxazole with oxazoleunder under conditions conditions sufficient sufficient to to form form compound compound G-9-a. G-9-a.

[0235]

[0235] In embodiments, someembodiments, In some the reaction the reaction conditions conditions comprise comprise a solvent, whereinwherein a solvent, the the solvent is solvent is tetrahydrofuran, tetrahydrofuran, 2-methyltetrahydrofuran, 2-methyltetrahydrofuran,or aor a mixture mixture thereof. thereof. In some In some embodiments, embodiments,

the solvent the solvent is is tetrahydrofuran and2-methyltetrahydrofuran. tetrahydrofuran and 2-methyltetrahydrofuran.

55

1004799942

[0236] In some

[0236] In some embodiments, embodiments, the reaction the reaction conditions conditions comprise comprise a metalating some agent.InIn some a metalatingagent. 2023206094 18 Jul 2023

embodiments, embodiments, thethe metalating metalating agent agent selected selected from from isopropyl isopropyl magnesium magnesium chloride, chloride, isopropyl isopropyl magnesiumbromide, magnesium bromide,TMPZnCl-LiCl, TMPZnCl-LiCl, TMPMgCl-LiCl, TMPMgCl-LiCl, and isopropyl and isopropyl magnesium magnesium

chloride/lithiumchloride chloride/lithium chloride(wherein (wherein TMPTMP refers refers to 2,2,6,6,-tetramethylpiperidine). to 2,2,6,6,-tetramethylpiperidine). In In some some embodiments, embodiments, thethe metalating metalating agent agent is isopropyl is isopropyl magnesium magnesium chloride. chloride. In some In some embodiments, embodiments, the the reaction conditions reaction conditionscomprise comprise contacting contacting the the oxazole oxazole and metalating and metalating agent agent at at -20 about about -20-10 °C to °C to -10 °C or °C or about about-15 -15°C. °C. In some

[0237] In some

[0237] embodiments, embodiments, the reaction the reaction conditions conditions comprise comprise adding adding ZnCl2. ZnCl. In some In some

embodiments, embodiments, thethe catalyst catalyst is is a palladium a palladium catalyst catalyst selected selected fromfrom Pd(PPh3)4, Pd(PPh), tBuXPhostBuXPhos Pd Pd precatalyst, XPhos precatalyst, XPhosPdPd precatalyst, precatalyst, RuPhos RuPhos Pd precatalyst, Pd precatalyst, and Pd-PEPPSI-IPent and Pd-PEPPSI-IPent (dichloro[1,3 (dichloro[1,3-

bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)). bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(1I). In some In some embodiments, embodiments, thethe catalyst catalyst is is Pd(PPh3)4. Pd(PPh). In embodiments, In some some embodiments, the mixture the reaction reactionismixture is heated to heated to greater than greater than about about5050°C°Cafter afteraddition additionof of ZnCl2. ZnCl. In some In some embodiments, embodiments, the reaction the reaction mixture mixture is is heated toto about heated about6060°C°Ctotoabout about 70 70 °C °C after after addition addition of ZnC2. of ZnCl.

[0238] SomeSome

[0238] embodiments embodiments provide for a for provide a process process of preparing of preparing a compound a compound (R)-G-1-a: (R)-G-1-a:

Br Br

O 1.10O

(R)-G-1-a (R)-G-1-a

comprising: comprising:

(a) contacting (a) compound contacting compound (R)-G-5-a (R)-G-5-a or an or an oxygen oxygen anion thereof: anion thereof:

OH OH O O

(R)-G-5-a (R)-G-5-a

with aa sulfonylating with sulfonylatingreagent reagentunder under conditions conditions sufficient sufficient to form to form compound compound (R)-G-6-a: (R)-G-6-a:

S 0 'O 6 0 o 0 O

(R)-G-6-a (R)-G-6-a

(b) contacting (b) compound contacting compound (R)-G-6-a (R)-G-6-a with awith a bromide bromide saltconditions salt under under conditions sufficient sufficient to form to form

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compound(R)-G-1-a. compound (R)-G-1-a. 2023206094 18 Jul 2023

[0239]

[0239] In In some embodiments, someembodiments, the sulfonylating the sulfonylating reagent reagent is methanesulfonyl is methanesulfonyl chloride. chloride.

In some

[0240] In some

[0240] embodiments, embodiments, the reaction the reaction conditions of of conditions step(a) step comprise aa base. (a) comprise In some base. In some

embodiments, embodiments, thethe base base is triethylamine, is triethylamine, diisopropylethylamine disopropylethylamine (Hunig's(Hunig's base), base), 1,8- 1,8 diazabicyclo[5.4.0]undec-7-ene, pyridine, diazabicyclo[5.4.0Jundec-7-ene, pyridine,oror dimethylaminopyridine dimethylaminopyridine(DMAP). (DMAP). In In some some

embodiments, embodiments, thethe base base is triethylamine. is triethylamine. In some In some embodiments, embodiments, the reaction the reaction conditions conditions of step of step (a) comprise (a) comprise a asolvent solventselected selectedfrom from 2-methyltetrahydrofuran, 2-methyltetrahydrofuran, tetrahydrofuran, tetrahydrofuran, and and dichloromethane.In In dichloromethane. some some embodiments, embodiments, the solvent the solvent is 2-methyltetrahydrofuran. is 2-methyltetrahydrofuran. In some In some embodiments, embodiments, thethe reaction reaction conditions conditions of step of step (a) (a) comprise comprise a promoter. a promoter. In someInembodiments, some embodiments, the promoter the promoter isisNal Nalorortetrabutylammonium tetrabutylammonium iodide. iodide. Inembodiments, In some some embodiments, the the reaction reaction conditions ofofstep conditions step (a) (a) comprise comprisea temperature a temperature of about of about 20to°Cabout 20 °C to about 30 °C.30In°C. In some some embodiments, embodiments, thethe reaction reaction conditions conditions of step of step (a) (a) comprise comprise a temperature a temperature of 22 of about about °C. 22 °C.

[0241] In some

[0241] In some embodiments, embodiments, the bromide salt salt the bromide is LiBr, is LiBr, NaBr, or or NaBr, KBr.InInsome KBr. some embodiments, embodiments, thethe bromide bromide salt salt is LiBr. is LiBr. In some In some embodiments, embodiments, the bromide the bromide salt is ansalt is an ammonium ammonium salt. InInsome salt. embodiments, some embodiments, the the bromide bromide salt salt is tetrabutylammonium is tetrabutylammonium bromide.bromide.

[0242] In some

[0242] In some embodiments, embodiments, the reaction step (b)acomprise of step (b)ofcomprise conditionsconditions the reaction a solvent solvent selected selected from N-methylpyrrolidone from N-methylpyrrolidone (NMP), (NMP),dimethylformamide dimethylformamide (DMF), (DMF), and and dimethylacetamide dimethylacetamide

(DMAc).InInsome (DMAc). someembodiments, embodiments,thethesolvent solventisis NMP. NMP.InInsome someembodiments, embodiments, In In some some

embodiments, embodiments, thethe reaction reaction conditions conditions of step of step (b) (b) comprise comprise a temperature a temperature of50 of about about °C to50about °C to about 60 °C. 60 °C. In In some someembodiments, embodiments, In some In some embodiments, embodiments, the reaction the reaction conditions conditions of of step (b) step (b) comprisea atemperature comprise temperature of about of about 55 55 °C. °C.

[0243] SomeSome

[0243] embodiments embodiments provide for a for provide a process process of preparing of preparing Compound Compound 1: 1: 0

N N N CO2H COH O 0 SS N N 0L O 110

oo O O

Compound 11 Compound or salt or salt or or co-crystal co-crystal thereof, thereof, comprising: comprising:

(a) contacting (a) contacting compound compoundG-2-a: G-2-a: 0 O Br Br / N N S IZ N O H H G-2-a G-2-a

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1004799942

with oxazole with oxazoleunder under conditions conditions sufficient sufficient to to form form compound compound G-9-a: G-9-a: 0 2023206094 18 Jul 2023

N O /1 N N S o IZ 0O N H H G-9-a G-9-a

(b) contacting (b) contactingcompound G-9-a with compound G-9-a with compound compound (R)-G-1-a: (R)-G-1-a:

Br Br

(R)-G-1-a (R)-G-1-a

underconditions under conditionssufficient sufficienttotoform form a compound a compound G-4-a: G-4-a:

0 NO N N Oo S I S N 0 i 0 N 0

O

G-4-a G-4-a

and (c) and (c) hydrolyzing hydrolyzing compound G-4-aunder compound G-4-a underconditions conditions sufficient sufficient totoform formCompound Compound 1.1.

[0244] In some

[0244] In some embodiments, embodiments, the reaction step (a) acomprise of step (a)ofcomprise conditionsconditions the reaction a solvent, solvent, wherein wherein the solvent the solvent is is tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydrofuran, 2-methyltetrahydrofuran, or aor a mixture mixture thereof. thereof. In In some some embodiments, embodiments, thethe solvent solvent is tetrahydrofuran is tetrahydrofuran and 2-methyltetrahydrofuran. and 2-methyltetrahydrofuran.

[0245] In some

[0245] In some embodiments, embodiments, the reaction the reaction conditions conditions of of step(a) step (a) comprise comprise aa metalating metalating agent. In agent. In some someembodiments, embodiments, the metalating the metalating agent agent selected selected from isopropyl from isopropyl magnesium magnesium chloride, chloride, isopropyl magnesium isopropyl bromide, TMPZnCl-LiCl, magnesium bromide, TMPZnCl-LiCl, TMPMgCl-LiCl, TMPMgCl-LiCl, and isopropyl and isopropyl magnesium magnesium

chloride/lithiumchloride chloride/lithium chloride(wherein (wherein TMPTMP refers refers to 2,2,6,6,-tetramethylpiperidine). to 2,2,6,6,-tetramethylpiperidine) In someIn some embodiments, embodiments, thethe metalating metalating agent agent is isopropyl is isopropyl magnesium magnesium chloride. chloride. In some In some embodiments, embodiments, the the reaction conditions reaction conditionsofofstep step(a) (a) comprise comprise contacting contacting the the oxazole oxazole and metalating and metalating agent agent at about at about -20 -20 °C to °C to -10 -10 °C °Cororabout about-15 -15°C.°C.

In some

[0246] In some

[0246] embodiments, embodiments, the reaction the reaction conditions of of conditions step(a) step comprise adding (a) comprise ZnCl2.InIn addingZnCl. someembodiments, some embodiments, the catalyst the catalyst is a ispalladium a palladium catalyst catalyst selected selected from Pd(PPh3)4, from Pd(PPh), tBuXPhos tBuXPhos Pd Pd precatalyst, XPhos precatalyst, XPhosPdPd precatalyst, precatalyst, RuPhos RuPhos Pd precatalyst, Pd precatalyst, and Pd-PEPPSI-IPent. and Pd-PEPPSI-IPent. In some In some embodiments, embodiments, thethe catalyst catalyst is is Pd(PPh3)4. Pd(PPh). In embodiments, In some some embodiments, the mixture the reaction reactionismixture is heated to heated to

58

1004799942

greater than greater about5050°C°Cafter than about afteraddition additionof of ZnCl2. ZnCl. In some In some embodiments, embodiments, the reaction the reaction mixture mixture is is 2023206094 18 Jul 2023

heated toto about heated about6060°C°Ctotoabout about 70 70 °C °C after after addition addition of ZnCl2. of ZnCl.

In some

[0247] In some

[0247] embodiments, embodiments, the reaction the reaction conditions of of conditions step(b) step base. In compriseaa base. (b)comprise In some some

embodiments, embodiments, thethe base base is sodium is sodium carbonate, carbonate, sodiumsodium bicarbonate, bicarbonate, potassium potassium carbonate,carbonate,

potassiumbicarbonate, potassium bicarbonate, cesium cesium carbonate, carbonate, cesium cesium bicarbonate, bicarbonate, potassium potassium phosphatephosphate tribasic, tribasic, or or potassiumphosphate potassium phosphate dibasic. dibasic. In some In some embodiments, embodiments, the basethe is base is carbonate, sodium sodium carbonate, sodium sodium bicarbonate, potassium bicarbonate, potassium carbonate, carbonate, potassium potassium bicarbonate, bicarbonate, cesiumcesium carbonate, carbonate, or or cesium cesium bicarbonate. InInsome bicarbonate. someembodiments, embodiments, the base the base is potassium is potassium carbonate. carbonate. In some In some embodiments, embodiments, the the base is base is potassium carbonate potassium carbonate or or potassium potassium bicarbonate. bicarbonate.

[0248] In some

[0248] In some embodiments, embodiments, the reaction step (b)acomprise of step (b)ofcomprise conditionsconditions the reaction a solvent solvent selected selected from N-methylpyrrolidone from N-methylpyrrolidone (NMP), (NMP),dimethylformamide dimethylformamide (DMF), (DMF), and and dimethylacetamide dimethylacetamide (DMA). (DMA).

In some In embodiments,the some embodiments, the solvent solvent is isNMP. NMP.

In some

[0249] In some

[0249] embodiments, embodiments, the reaction the reaction conditions of of conditions step(b) step compriseaa temperature (b)comprise of temperature of about 100 about 100°C°Ctotoabout about 140140 °C. °C. In some In some embodiments, embodiments, the reaction the reaction conditions conditions of of step (b) step (b) comprisea atemperature comprise temperature of about of about 115 115 °C. °C. In some

[0250] In some

[0250] embodiments, embodiments, the reaction the reaction conditions of of conditions step(c) step comprise ananacid. (c) comprise In some acid. In some

embodiments, embodiments, thethe acid acid is sulfuric is sulfuric acid,tetrafluoroboric acid, tetrafluoroboric acid, acid, methanesulfonic methanesulfonic acid,acid, nitric nitric acid,acid, or or hydrochloricacid. hydrochloric acid.InInsome some embodiments, embodiments, the is the acid acid is sulfuric sulfuric acid.acid. In some In some embodiments, embodiments, the the acid is acid is hydrochloric acid. hydrochloric acid.

In some

[0251] In some

[0251] embodiments, embodiments, the reaction the reaction step (c) acomprise of step (c)ofcomprise conditionsconditions a co-solvent. co-solvent. In In someembodiments, some embodiments, the co-solvent the co-solvent is anisalcohol. an alcohol. In embodiments, In some some embodiments, the co-solvent the co-solvent is 2- is 2 propanol,t-butanol, propanol, t-butanol, t-amyl t-amylalcohol, alcohol,ethanol, ethanol, or or acetonitrile. acetonitrile.

In some

[0252] In some

[0252] embodiments, embodiments, the reaction the reaction conditions of of conditions step(c) step comprise aa temperature (c) comprise of temperature of about 55 and about and1010°C.°C.In In some some embodiments, embodiments, the reaction the reaction conditions conditions of step of (c)step (c) comprise comprise a a temperaturebetween temperature between about about 0 about 0 and and about 20In°C. 20 °C. someInembodiments, some embodiments, theconditions the reaction reaction conditions of of step (c) step (c) comprise between comprise between about about 2 and 2 and about about 8 °C.8 °C.

[0253] SomeSome

[0253] embodiments embodiments provide for a for provide a process process of preparing of preparing Compound Compound 1: 1:

N EN ~ X NYCO2H N COH 0 S N O

00 o O

Compound 11 Compound

59

1004799942

or aa salt or salt or or co-crystal co-crystal thereof, thereof, comprising: comprising: 2023206094 18 Jul 2023

(a) contacting (a) contactingcompound (R)-G-6-a: compound (R)-G-6-a:

6'6S, O S

0 O 0 O

(R)-G-6-a (R)-G-6-a

with aa bromide with bromidesalt saltunder underconditions conditions sufficient sufficient to to form form compound compound (R)-G-1-a: (R)-G-1-a:

Br Br

O O

(R)-G-1-a (R)-G-1-a

(b) contacting (b) contacting compound compoundG-2-a: G-2-a: 0 O Br Br / N N S S N IZ -OO0 N H O H G-2-a G-2-a with oxazole with oxazoleunder under conditions conditions sufficient sufficient to to form form compound compound G-9-a: G-9-a: 0 O N N N o O N O S IZ O N H H G-9-a G-9-a

(c) contacting (c) compound contacting compound G-9-a G-9-a with with compound compound (R)-G-1-a(R)-G-1-a under sufficient under conditions conditions tosufficient form a to form a G-4-a: compoundG-4-a: compound

0

LNI N N O

O S O N 0 o o 01o~

O

G-4-a G-4-a

and (d) and (d) hydrolyzing hydrolyzing compound G-4-aunder compound G-4-a underconditions conditions sufficient sufficient totoform formCompound Compound 1.1.

60

1004799942

[0254] In some

[0254] In some embodiments, embodiments, the bromide salt salt the bromide is LiBr, is LiBr, NaBr, or or NaBr, KBr. some KBr.InInsome 2023206094 18 Jul 2023

embodiments, embodiments, thethe bromide bromide salt salt is LiBr. is LiBr. In some In some embodiments, embodiments, the bromide the bromide salt is ansalt is an ammonium ammonium salt. InInsome salt. embodiments, some embodiments, the the bromide bromide salt salt is tetrabutylammonium is tetrabutylammonium bromide.bromide.

[0255] In some

[0255] In some embodiments, embodiments, the reaction step (a) acomprise of step (a)ofcomprise conditionsconditions the reaction a solvent solvent selected selected from N-methylpyrrolidone from N-methylpyrrolidone (NMP), (NMP),dimethylformamide dimethylformamide (DMF), (DMF), and and dimethylacetamide dimethylacetamide

(DMAc).InInsome (DMAc). someembodiments, embodiments,thethe solventisis NMP. solvent NMP.InInsome someembodiments, embodiments, In In some some

embodiments, embodiments, thethe reaction reaction conditions conditions of step of step (a) (a) comprise comprise a temperature a temperature of 50 of about about °C to50about C to about 60 °C. 60 C. In In some someembodiments, embodiments, In some In some embodiments, embodiments, the reaction the reaction conditions conditions ofcomprise of step (a) step (a) comprise a temperature a temperatureofofabout about55 55 °C.C.

[0256] In some

[0256] In some embodiments, embodiments, the bromide salt salt the bromide is LiBr, is LiBr, NaBr, or or NaBr, KBr. some KBr.InInsome embodiments, embodiments, thethe bromide bromide salt salt is LiBr. is LiBr. In some In some embodiments, embodiments, the bromide the bromide salt is ansalt is an ammonium ammonium salt. InInsome salt. embodiments, some embodiments, the the bromide bromide salt salt is tetrabutylammonium is tetrabutylammonium bromide.bromide.

[0257] In some

[0257] In some embodiments, embodiments, the reaction the reaction conditions of of conditions step (b)comprise step(b) solvent, wherein compriseaa solvent, wherein

the solvent the solvent is is tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydrofuran, 2-methyltetrahydrofuran, or aor a mixture mixture thereof thereof. In In some some embodiments, embodiments, thethe solvent solvent is tetrahydrofuran is tetrahydrofuran and 2-methyltetrahydrofuran. and 2-methyltetrahydrofuran.

[0258] In some

[0258] In some embodiments, embodiments, the reaction the reaction conditions conditions of of step(b) step (b) comprise compriseaa metalating metalating agent. In agent. In some someembodiments, embodiments, the metalating the metalating agent agent selected selected from isopropyl from isopropyl magnesium magnesium chloride, chloride, isopropyl magnesium isopropyl bromide,TMPZnCl-LiCl, magnesium bromide, TMPZnCl-LiCl, TMPMgCl-LiCl, TMPMgCl-LiCl, and isopropyl and isopropyl magnesium magnesium

chloride/lithiumchloride chloride/lithium chloride(wherein (wherein TMPTMP refers refers to 2,2,6,6,-tetramethylpiperidine). to 2,2,6,6,-tetramethylpiperidine). In In some some embodiments, embodiments, thethe metalating metalating agent agent is isopropyl is isopropyl magnesium magnesium chloride. chloride. In some In some embodiments, embodiments, the the reaction conditions reaction conditionsofofstep step(b) (b)comprise comprise contacting contacting the the oxazole oxazole and metalating and metalating agent agent at at about about -20 °CCtoto -10 -20 -10 °CCororabout about-15-15°C.C. In some

[0259] In some

[0259] embodiments, embodiments, the reaction the reaction conditions of of conditions step (b)comprise step(b) compriseadding ZnCl2.InIn addingZnCl. someembodiments, some embodiments, the catalyst the catalyst is a ispalladium a palladium catalyst catalyst selected selected from Pd(PPh3)4, from Pd(PPh), tBuXPhos tBuXPhos Pd Pd precatalyst, XPhos precatalyst, XPhosPdPd precatalyst, precatalyst, RuPhos RuPhos Pd precatalyst, Pd precatalyst, and Pd-PEPPSI-IPent. and Pd-PEPPSI-IPent. In some In some embodiments, embodiments, thethe catalyst catalyst is is Pd(PPhIn3)some Pd(PPh). 4. In embodiments, some embodiments, the mixture the reaction reactionismixture is heated to heated to greater than greater than about about5050°C Cafter afteraddition additionofof ZnCl2. ZnCl. In some In some embodiments, embodiments, the reaction the reaction mixture mixture is is heated toto about heated about6060°C Ctotoabout about 70 70 C after °C after addition addition of ZnC2. of ZnCl.

In some

[0260] In some

[0260] embodiments, embodiments, the reaction the reaction conditions of of conditions step(c) step (c) comprise base. In comprise aa base. In some some

embodiments, embodiments, thethe base base is sodium is sodium carbonate, carbonate, sodiumsodium bicarbonate, bicarbonate, potassium potassium carbonate,carbonate,

potassiumbicarbonate, potassium bicarbonate, cesium cesium carbonate, carbonate, cesium cesium bicarbonate, bicarbonate, potassium potassium phosphatephosphate tribasic, tribasic, or or potassiumphosphate potassium phosphate dibasic. dibasic. In some In some embodiments, embodiments, the basethe is base is carbonate, sodium sodium carbonate, sodium sodium bicarbonate, potassium bicarbonate, potassium carbonate, carbonate, potassium potassium bicarbonate, bicarbonate, cesiumcesium carbonate, carbonate, cesium bicarbonate, cesium bicarbonate,

potassiumphosphate potassium phosphate tribasic, tribasic, or or potassium potassium phosphate phosphate dibasic. dibasic. In embodiments, In some some embodiments, the the base is base is sodiumcarbonate, sodium carbonate,sodium sodium bicarbonate, bicarbonate, potassium potassium carbonate, carbonate, potassium potassium bicarbonate, bicarbonate, cesium cesium

61

1004799942

carbonate, ororcesium carbonate, cesiumbicarbonate. bicarbonate. In In some some embodiments, embodiments, theisbase the base is potassium potassium carbonate. carbonate. In In 2023206094 18 Jul 2023

someembodiments, some embodiments, the base the base is potassium is potassium carbonate carbonate or potassium or potassium bicarbonate. bicarbonate.

[0261] In some

[0261] In some embodiments, embodiments, the reaction step (c) acomprise of step (c)ofcomprise conditionsconditions the reaction a solvent solvent selected selected from N-methylpyrrolidone from N-methylpyrrolidone (NMP), (NMP),dimethylformamide dimethylformamide (DMF), (DMF), and and dimethylacetamide dimethylacetamide (DMA). (DMA).

In some In embodiments,the some embodiments, the solvent solvent is isNMP. NMP.

In some

[0262] In some

[0262] embodiments, embodiments, the reaction the reaction conditions of of conditions step(c) step comprise aa temperature (c) comprise of temperature of about 9090°C°Ctotoabout about about100100 °C.°C. In In some some embodiments, embodiments, the reaction the reaction conditions conditions of step of step (c) (c) comprise comprise

a temperature a temperature ofofabout about100100 C to °C to about about 140 140 C.some °C. In In some embodiments, embodiments, the reaction the reaction conditions conditions of of step (c) step (c) comprise comprise a atemperature temperatureof of about about 115 115 °C. C. In some

[0263] In some

[0263] embodiments, embodiments, the reaction the reaction conditions of of conditions step(d) step compriseananacid. (d) comprise In some acid. In some

embodiments, embodiments, thethe acid acid is sulfuric is sulfuric acid,tetrafluoroboric acid, tetrafluoroboric acid, acid, methanesulfonic methanesulfonic acid,acid, nitric nitric acid,acid, or or hydrochloricacid. hydrochloric acid.InInsome some embodiments, embodiments, the is the acid acid is sulfuric sulfuric acid.acid. In some In some embodiments, embodiments, the the acid is acid is hydrochloric acid. hydrochloric acid.

In some

[0264] In some

[0264] embodiments, embodiments, the reaction the reaction step (d) acomprise of step (d)ofcomprise conditionsconditions a co-solvent. co-solvent. In In someembodiments, some embodiments, the co-solvent the co-solvent is anisalcohol. an alcohol. In embodiments, In some some embodiments, the co-solvent the co-solvent is 2- is 2 propanol,t-butanol, propanol, t-butanol, t-amyl t-amylalcohol, alcohol,ethanol, ethanol, or or acetonitrile. acetonitrile.

In some

[0265] In some

[0265] embodiments, embodiments, the reaction the reaction conditions of of conditions step(d) step compriseaa temperature (d) comprise of temperature of about 55 and about and1010°C.°C.In In some some embodiments, embodiments, the reaction the reaction conditions conditions of step of (d)step (d) comprise comprise a a temperaturebetween temperature between about about 0 and 0 and aboutabout 20In°C. 20 °C. someInembodiments, some embodiments, theconditions the reaction reaction conditions of of step (e) step (e) comprise between comprise between about about 2 and 2 and about about 8 °C.8 °C.

[0266] SomeSome

[0266] embodiments embodiments provide for a for provide a process process of preparing of preparing Compound Compound 1: 1:

N 0 SS N -- 0 N N XCOH CO 2H

O N O O O

Compound 11 Compound or salt or salt or or co-crystal co-crystal thereof, thereof, comprising: comprising:

(a) contacting (a) compound contacting compound (R)-G-5-a (R)-G-5-a or an or an oxygen oxygen anion thereof: anion thereof:

OH OH

0 O 0 O

(R)-G-5-a (R)-G-5-a

62

1004799942

with aa sulfonylating with sulfonylatingreagent reagentunder under conditions conditions sufficient sufficient to form to form compound compound (R)-G-6-a: (R)-G-6-a:

2023

S 6\ 0

, 2023206094 18 Jul

O

(R)-G-6-a (R)-G-6-a

(b) contacting (b) compound contacting compound (R)-G-6-a (R)-G-6-a with awith a bromide bromide saltconditions salt under under conditions sufficient sufficient to form to form compound(R)-G-1-a: compound (R)-G-1-a: Br Br

O O

(R)-G-1-a (R)-G-1-a

(c) contacting (c) contacting compound compoundG-2-a: G-2-a: 0

Br Br / N N S S N IZ -OO0 N H O H G-2-a G-2-a with oxazole with oxazoleunder under conditions conditions sufficient sufficient to to form form compound compound G-9-a: G-9-a: 0 O N N N o O N O S IZ O N H H G-9-a G-9-a (d) contacting (d) compound contacting compound G-9-a G-9-a with with compound compound (R)-G-1-a(R)-G-1-a under sufficient under conditions conditions tosufficient form a to form a G-4-a: compoundG-4-a: compound

0

LNI N N O

O S N 0 01o~ o o

O

G-4-a G-4-a

and (e) and (e) hydrolyzing hydrolyzing compound G-4-aunder compound G-4-a underconditions conditions sufficient sufficient totoform formCompound Compound 1.1.

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1004799942

[0267]

[0267] In In some embodiments, someembodiments, the sulfonylating the sulfonylating reagent reagent is methanesulfonyl is methanesulfonyl chloride. chloride. 2023206094 18 Jul 2023

[0268]

[0268] In In some embodiments, someembodiments, the reaction the reaction conditions conditions of (a) of step stepcomprise a base.a In (a) comprise some In some base. embodiments, embodiments, thethe base base is triethylamine, is triethylamine, diisopropylethylamine disopropylethylamine (Hunig's(Hunig's base), base), 1,8- 1,8 diazabicyclo[5.4.0]undec-7-ene, pyridine, diazabicyclo[5.4.0Jundec-7-ene, pyridine,oror dimethylaminopyridine dimethylaminopyridine(DMAP). (DMAP). In In some some

embodiments, embodiments, thethe base base is triethylamine. is triethylamine. In some In some embodiments, embodiments, the reaction the reaction conditions conditions of step of step (a) comprise (a) comprise a asolvent solventselected selectedfrom from 2-methyltetrahydrofuran, 2-methyltetrahydrofuran, tetrahydrofuran, tetrahydrofuran, and and dichloromethane.In In dichloromethane. some some embodiments, embodiments, the solvent the solvent is 2-methyltetrahydrofuran. is 2-methyltetrahydrofuran. In some In some embodiments, embodiments, thethe reaction reaction conditions conditions of step of step (a) (a) comprise comprise a promoter. a promoter. In someInembodiments, some embodiments, the promoter the promoter isisNal Nalorortetrabutylammonium tetrabutylammonium iodide. iodide. Inembodiments, In some some embodiments, the the reaction reaction conditions ofofstep conditions step (a) (a) comprise comprisea temperature a temperature of about of about 20to°Cabout 20 °C to about 30 °C.30In°C. In some some embodiments, embodiments, thethe reaction reaction conditions conditions of step of step (a) (a) comprise comprise a temperature a temperature of 22 of about about °C. 22 °C.

[0269] In some

[0269] In some embodiments, embodiments, the bromide salt salt the bromide is LiBr, is LiBr, NaBr, or or NaBr, KBr. some KBr.InInsome embodiments, embodiments, thethe bromide bromide salt salt is LiBr. is LiBr. In some In some embodiments, embodiments, the bromide the bromide salt is ansalt is an ammonium ammonium salt. InInsome salt. embodiments, some embodiments, the the bromide bromide salt salt is tetrabutylammonium is tetrabutylammonium bromide.bromide.

[0270] In some

[0270] In some embodiments, embodiments, the reaction step (b)acomprise of step (b)ofcomprise conditionsconditions the reaction a solvent solvent selected selected from N-methylpyrrolidone from N-methylpyrrolidone (NMP), (NMP),dimethylformamide dimethylformamide (DMF), (DMF), and and dimethylacetamide dimethylacetamide

(DMAc).InInsome (DMAc). someembodiments, embodiments,thethe solventisis NMP. solvent NMP.InInsome someembodiments, embodiments, In In some some

embodiments, embodiments, thethe reaction reaction conditions conditions of step of step (b) (b) comprise comprise a temperature a temperature of50 of about about °C to50about °C to about 60 °C. 60 °C. In In some someembodiments, embodiments, In some In some embodiments, embodiments, the reaction the reaction conditions conditions of of step (b) step (b) comprisea atemperature comprise temperature of about of about 55 55 °C. °C.

[0271] In some

[0271] In some embodiments, embodiments, the reaction step (c) acomprise of step (c)ofcomprise conditionsconditions the reaction a solvent, solvent, wherein wherein the solvent the solvent is is tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydrofuran, 2-methyltetrahydrofuran, or aor a mixture mixture thereof. thereof. In In some some embodiments, embodiments, thethe solvent solvent is tetrahydrofuran is tetrahydrofuran and 2-methyltetrahydrofuran. and 2-methyltetrahydrofuran.

[0272] In some

[0272] In some embodiments, embodiments, the reaction the reaction conditions conditions of of step(c) step (c) comprise comprise aa metalating metalating agent. In agent. In some someembodiments, embodiments, the metalating the metalating agent agent selected selected from isopropyl from isopropyl magnesium magnesium chloride, chloride, isopropyl magnesium isopropyl bromide, TMPZnCl-LiCl, magnesium bromide, TMPZnCl-LiCl, TMPMgCl-LiCl, TMPMgCl-LiCl, and isopropyl and isopropyl magnesium magnesium

chloride/lithiumchloride chloride/lithium chloride(wherein (wherein TMPTMP refers refers to 2,2,6,6,-tetramethylpiperidine). to 2,2,6,6,-tetramethylpiperidine). In In some some embodiments, embodiments, thethe metalating metalating agent agent is isopropyl is isopropyl magnesium magnesium chloride. chloride. In some In some embodiments, embodiments, the the reaction conditions reaction conditionsofofstep step(c) (c) comprise comprise contacting contacting the the oxazole oxazole and metalating and metalating agent agent at at about about -20 °CCtoto -10 -20 -10 °CCororabout about-15-15°C.C. In some

[0273] In some

[0273] embodiments, embodiments, the reaction the reaction conditions of of conditions step (c) comprise step(c) comprise adding ZnCl2.InIn addingZnCl. someembodiments, some embodiments, the catalyst the catalyst is a ispalladium a palladium catalyst catalyst selected selected from Pd(PPh3)4, from Pd(PPh), tBuXPhos tBuXPhos Pd Pd precatalyst, XPhos precatalyst, XPhosPdPd precatalyst, precatalyst, RuPhos RuPhos Pd precatalyst, Pd precatalyst, and Pd-PEPPSI-IPent. and Pd-PEPPSI-IPent. In some In some embodiments, embodiments, thethe catalyst catalyst is is Pd(PPh3)4. Pd(PPh). In embodiments, In some some embodiments, the mixture the reaction reactionismixture is heated to heated to

64

1004799942

greater than greater about5050°C Cafter than about afteraddition additionofof ZnCl2. ZnCl. In some In some embodiments, embodiments, the reaction the reaction mixture mixture is is 2023206094 18 Jul 2023

heated toto about heated about6060°C Ctotoabout about 70 70 C after °C after addition addition of ZnCl2. of ZnCl.

In some

[0274] In some

[0274] embodiments, embodiments, the reaction the reaction conditions of of conditions step(d) step base. In compriseaa base. (d) comprise In some some

embodiments, embodiments, thethe base base is sodium is sodium carbonate, carbonate, sodiumsodium bicarbonate, bicarbonate, potassium potassium carbonate,carbonate,

potassiumbicarbonate, potassium bicarbonate, cesium cesium carbonate, carbonate, cesium cesium bicarbonate, bicarbonate, potassium potassium phosphatephosphate tribasic, tribasic, or or potassiumphosphate potassium phosphate dibasic. dibasic. In some In some embodiments, embodiments, the basethe is base is carbonate, sodium sodium carbonate, sodium sodium bicarbonate, potassium bicarbonate, potassium carbonate, carbonate, potassium potassium bicarbonate, bicarbonate, cesiumcesium carbonate, carbonate, cesium bicarbonate, cesium bicarbonate,

potassiumphosphate potassium phosphate tribasic, tribasic, or or potassium potassium phosphate phosphate dibasic. dibasic. In embodiments, In some some embodiments, the the base is base is sodiumcarbonate, sodium carbonate,sodium sodium bicarbonate, bicarbonate, potassium potassium carbonate, carbonate, potassium potassium bicarbonate, bicarbonate, cesium cesium carbonate, ororcesium carbonate, cesiumbicarbonate. bicarbonate. In some In some embodiments, embodiments, theisbase the base is potassium potassium carbonate. carbonate. In In someembodiments, some embodiments, the base the base is potassium is potassium carbonate carbonate or potassium or potassium bicarbonate. bicarbonate.

[0275] In some

[0275] In some embodiments, embodiments, the reaction step (d)acomprise of step (d)ofcomprise conditionsconditions the reaction a solvent solvent selected selected from N-methylpyrrolidone from N-methylpyrrolidone (NMP), (NMP),dimethylformamide dimethylformamide (DMF), (DMF), and and dimethylacetamide dimethylacetamide (DMA). (DMA).

In some In embodiments,the some embodiments, the solvent solvent is isNMP. NMP.

In some

[0276] In some

[0276] embodiments, embodiments, the reaction the reaction conditions of of conditions step(d) step compriseaa temperature (d) comprise of temperature of about 9090°C°Ctotoabout about about100100 °C.°C. In some In some embodiments, embodiments, the reaction the reaction conditions conditions of step of step (d) (d) comprise comprise

a temperature a temperatureofofabout about100100 C to °C to about about 140 140 C.some °C. In In some embodiments, embodiments, the reaction the reaction conditions conditions of of step (d) step (d) comprise comprise a atemperature temperatureof of about about 115 115 °C. C.

[0277] In some

[0277] In some embodiments, embodiments, the reaction the reaction conditions of of conditions step comprise ananacid. (e) comprise step(e) In some acid. In some embodiments, embodiments, thethe acid acid is sulfuric is sulfuric acid,tetrafluoroboric acid, tetrafluoroboric acid, acid, methanesulfonic methanesulfonic acid,acid, nitric nitric acid,acid, or or hydrochloricacid. hydrochloric acid.InInsome some embodiments, embodiments, the is the acid acid is sulfuric sulfuric acid.acid. In some In some embodiments, embodiments, the the acid is acid is hydrochloric acid. hydrochloric acid.

[0278] some embodiments, In embodiments,

[0278] In some the reaction step (e) acomprise of step (e)ofcomprise conditionsconditions the reaction a co-solvent. co-solvent. In In someembodiments, some embodiments, the co-solvent the co-solvent is anisalcohol. an alcohol. In embodiments, In some some embodiments, the co-solvent the co-solvent is 2- is 2 propanol, t-butanol,t-amyl propanol, t-butanol, t-amylalcohol, alcohol,ethanol, ethanol, or or acetonitrile. acetonitrile.

In some

[0279] In some

[0279] embodiments, embodiments, the reaction the reaction conditions of of conditions step(e) step comprise aa temperature (e) comprise of temperature of about55 and about and1010°C.°C.In In some some embodiments, embodiments, the reaction the reaction conditions conditions of step of (e)step (e) comprise comprise a a temperaturebetween temperature between about about 0 about 0 and and about 20In°C. 20 °C. someInembodiments, some embodiments, theconditions the reaction reaction conditions of of step (e) step (e) comprise between comprise between about about 2 and 2 and about about 8 °C.8 °C. 5. Intermediate 5. Compounds Intermediate Compounds

[0280] SomeSome

[0280] embodiments embodiments provide hereinherein provide intermediates intermediates useful useful thethe for for synthesisofof synthesis

Compound Compound 1 or 1 or methods methods of of making making such such intermediates. intermediates.

[0281] SomeSome

[0281] embodiments embodiments provide for a for provide a compound compound of formula, G-4-a:G-4-a: of formula,

65

1004799942

0 2023206094 18 Jul 2023

N O N O S N *0

o OO

G-4-a. G-4-a.

[0282] SomeSome

[0282] embodiments embodiments provide for a for provide a compound compound of formula, of formula, G-4-b:G-4-b: O O OBn N OBn N O S O N O.0 O oO oO

G-4-b. G-4-b.

102831 SomeSome

[0283] embodiments embodiments provide for a for provide acompound compound of formula, of formula, (R)-G-8: (R)-G-8:

[acyl]'O

[acyl].

O o 0 Rª O Ra R20 R² -Rs

(R)-G-8 (R)-G-8 R wherein: wherein:

[acyl] is

[acyl] is RxC(O)-, wherein R*C(O)-, wherein RX Rx is is optionally optionally substituted substituted C1-4 C1-4 aliphatic; aliphatic;

R is Rª is an an optionally optionally substituted substitutedgroup groupselected selected from from a 3-7 a 3-7 membered membered ring having ring having 0-2 heteroatoms 0-2 heteroatoms

selected from selected fromnitrogen, nitrogen,oxygen, oxygen, andand sulfur, sulfur, andand a C1-6 a C1-6 aliphatic; aliphatic;

R2 is R² is hydrogen, hydrogen, ororoptionally optionallysubstituted substituted C1-6 aliphatic;and C1-6aliphatic; and R'isishydrogen R hydrogenor or halogen. halogen.

In some

[0284] In some

[0284] embodiments, embodiments, Rx is optionally Rx is optionally substituted substituted C3-4 aliphatic. C3-4 aliphatic.

[0285] SomeSome

[0285] embodiments embodiments provide for a for provide a compound compound of formula of formula (R)-I-1: (R)-I-1:

0 O RX R* O Rj O o O 0O

(R)-I-1. (R)-I-1.

66

1004799942

whereinRXRx wherein isisoptionally optionallysubstituted substitutedC1-4aliphatic. C1-4 aliphatic. 2023206094 18 Jul 2023

[0286] SomeSome

[0286] embodiments embodiments provide for a for provide a compound compound of formula of formula (R)-I-2: (R)-I-2:

0 O Rx U'O RX o O 0 O O

(R)-I-2 (R)-I-2

whereinRxRxisisoptionally wherein optionallysubstituted substitutedC1-4aliphatic. C1-4 aliphatic.

[0287] SomeSome

[0287] embodiments embodiments provide for a for provide a compound compound of formula of formula (R)-G-1: (R)-G-1:

RH RH O Rª 00R R²·O ~RB

(R)-G-1 (R)-G-1 R wherein: wherein:

RHisis aa leaving RH leaving group; group; R is Rª is an optionally substituted an optionally substitutedgroup group selected selected from from aa 3-7 memberedring 3-7 membered ringhaving having0-20-2 heteroatomsselected heteroatoms selectedfrom from nitrogen, nitrogen, oxygen, oxygen, and sulfur, and sulfur, and aand C1-6aC1-6aliphatic; aliphatic;

R2 is R² is hydrogen, hydrogen, ororoptionally optionallysubstituted substitutedC1-6aliphatic; and C1-6 aliphatic; and

R5isishydrogen R hydrogenor or halogen. halogen.

[0288] SomeSome

[0288] embodiments embodiments provide for a for provide a compound compound of formula of formula H-1: H-1: RH o 0 O O O

H-1 H-1 whereinRHRH wherein is is a aleaving leavinggroup. group.

[0289] SomeSome

[0289] embodiments embodiments provide for a for provide a compound compound of formula of formula H-2: H-2: RH

O 0 o 0 O

H-2 H-2 whereinRHRH wherein is is a aleaving leavinggroup. group.

67

1004799942

[0290]

[0290] In some embodiments, embodiments, In some RH isRH is halogen halogen or sulfonate. In In or sulfonate. some some embodiments, embodiments, RH RH is is 2023206094 18 Jul 2023

bromo.InInsome bromo. some embodiments, embodiments, RH is RHis mesylate. mesylate. In someInembodiments, some embodiments, [acyl] is succinyl.

[acyl] is succinyl. In some In some embodiments, embodiments, thethe [acyl]

[acyl] donor donor is succinic is succinic anhydride. anhydride.

[0291] SomeSome

[0291] embodiments embodiments provide for a for provide a compound compound of formula: of formula:

0 HOO HO

o a , or a salt thereof , or a salt thereof.

[0292] SomeSome

[0292] embodiments embodiments provide for a for provide a compound compound of formula: of formula:

0 HO HO O

0 o O O or a salt thereof. , or a salt thereof.

6. Uses, 6. Uses, formulation formulation and administration and and administration andpharmaceutically acceptable compositions pharmaceutically acceptable compositions

[0293] According

[0293] According to another to another embodiment, embodiment, the the invention invention provides provides a composition a composition comprising comprising

a compound a compound of of this this invention invention or aorpharmaceutically a pharmaceutically acceptable acceptable salt, ester, salt, ester, or salt or salt of ester of ester thereof thereof

and aa pharmaceutically and pharmaceutically acceptable acceptable carrier, carrier, adjuvant, adjuvant, or vehicle. or vehicle. SomeSome embodiments embodiments provide provide for for a composition a compositioncomprising comprising a compound a compound as described as described herein, herein, or a pharmaceutically or a pharmaceutically acceptableacceptable salt salt or co-crystal or thereof, and co-crystal thereof, and aa pharmaceutically pharmaceutically acceptable acceptable carrier, carrier, adjuvant, adjuvant, or vehicle. or vehicle.

[0294] SomeSome

[0294] embodiments embodiments provide for a for provide a composition composition comprising comprising a crystalline a crystalline form form of of Compound Compound 1 as1described as described herein. herein. The amount The amount of compound of compound in compositions in compositions of thisisinvention of this invention is such that such that is is effective effective to to measurably inhibitACC, measurably inhibit ACC,in ainbiological a biological sample sample or inora in a patient. patient. In In certain embodiments, certain embodiments, thethe amount amount of compound of compound in compositions in compositions of this invention of this invention is such is such that is that is effective to effective to measurably inhibitACC, measurably inhibit ACC,in ainbiological a biological sample sample or inor a in a patient. patient. In certain In certain

embodiments, embodiments, a composition a composition of this of this invention invention is formulated is formulated for administration for administration to a patient to a patient in in needofofsuch need suchcomposition. composition.In In some some embodiments, embodiments, a composition a composition of this invention of this invention is formulated is formulated

for oral for oral administration to aa patient. administration to patient. termterm

[0295] The The

[0295] "compound" "compound" as used as used herein, herein, meansmeans an ACC ACC inhibitor an inhibitor of Formula of Formula I I (including but (including butnot notlimited limitedtotoCompound Compound 1),a orsolid 1), or a solid formform thereof thereof. In some In some embodiments, embodiments, the the term "compound" term "compound" as used as used herein, herein, meansmeans an ACC an ACC inhibitor inhibitor of IFormula of Formula I (including (including but not but not limited to limited to Compound Compound 1), 1), or aorsalt a salt or or solid solid form form thereof. thereof. In some In some embodiments, embodiments, a compound a compound is is Compound Compound 1 ora apharmaceutically 1 or pharmaceutically acceptable acceptable salt salt thereof. thereof.InInsome someembodiments, embodiments, aa compound compound

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is the is the free free acid acid of of Compound 1. some Compound 1. In In some embodiments, embodiments, a compound a compound is a solid is a solid form of form of 2023206094 18 Jul 2023

Compound Compound 1. 1.InIn some some embodiments, embodiments, a compound a compound is a iscrystalline a crystallineform formofofCompound Compound 1. 1. In In some embodiments, some embodiments,a acompound compoundis is Form Form I, I,Form FormII,II,Form FormIII, III, Form FormIV, IV, Form FormV,V,Form FormVI, VI, FormVII, Form VII, or or Form VIII of Form VIII of Compound Compound 1.1.InInsome someembodiments, embodiments, a compound a compound is aispolymorph a polymorph of of the free the freeacid acidofof Compound 1. In Compound 1. In some some embodiments, embodiments, aa compound compoundisisForm FormI,I, Form FormVII, VII, or or Form Form VIII of VIII of Compound Compound 1.1. In Insome someembodiments, embodiments,a compound a compound is ais pseudopolymorph a pseudopolymorph of the of the free free acid acid

of Compound of Compound 1.1.InInsome someembodiments, embodiments, a compound a compound is Form is Form I ofI of Compound Compound 1. In1. some In some embodiments, aa compound embodiments, compoundis isForm FormII IIof ofCompound Compound1. 1. In In some some embodiments, embodiments, a compound a compound is is FormIII Form III of of Compound Compound 1.1. InInsome someembodiments, embodiments, a compound a compound is Form is Form IV Compound IV of of Compound 1. In 1. In some embodiments, some embodiments,a acompound compoundis is Form Form V of V of Compound Compound 1. In1. some In some embodiments, embodiments, a a compoundisis Form compound FormVIVIofofCompound Compound 1. some 1. In In some embodiments, embodiments, a compound a compound is Form is Form VII VII of of Compound Compound 1. 1.InIn some some embodiments, embodiments, a compound a compound is Form is Form VIIIVIII of Compound of Compound 1. In 1.some In some embodiments,aa compound embodiments, compoundis isa asolvate solvate of of Compound Compound 1.1.In In some someembodiments, embodiments,a compound a compound is is amorphousCompound amorphous Compound 1. In 1. In some some embodiments, embodiments, a compound a compound is a is a salt salt or or co-crystal of co-crystal of Compound Compound 1. 1.InInsome someembodiments, embodiments, a compound a compound is Compound is Compound 1 Sodium 1 Sodium Form Form I. I. In In some some embodiments,aa compound embodiments, compoundis isCompound Compound 1 Sodium 1 Sodium FormForm II. some II. In In some embodiments, embodiments, a a compoundisis Compound compound Compound 1 Calcium 1 Calcium Form Form I. In I. In some some embodiments, embodiments, a compound a compound is Compound is Compound 1 1 MagnesiumForm Magnesium Form I. I.InInsome someembodiments, embodiments, a compound a compound is Compound is Compound 1 Diethanolamine 1 Diethanolamine Form I. Form I.

In some In embodiments,aa compound some embodiments, compoundis isCompound Compound 1 Piperazine 1 Piperazine Form Form I. I.

[0296] termterm

[0296] The The as as "patient," "patient," herein, means usedherein, used preferably aa mammal, animal, preferably meansanananimal, mammal, and most andmost preferably aa human. preferably human. term "pharmaceutically The "pharmaceutically

[0297] The term

[0297] acceptable acceptable carrier, adjuvant, carrier, adjuvant, or diluent" diluent" or refers to refers a non- to a non toxic carrier, toxic carrier, adjuvant, or vehicle adjuvant, or that does vehicle that does not notdestroy destroythe thepharmacological pharmacological activity activity of the of the

compound compound with with which which it isitformulated. is formulated. Pharmaceutically Pharmaceutically acceptable acceptable carriers,carriers, adjuvantsadjuvants or or diluents that diluents that may may bebeused usedininthethecompositions compositions of this of this invention invention include, include, but not but are are limited not limited to, to, antiadherents, binders, antiadherents, binders, coatings, coatings,colorants, colorants,disintegrants, disintegrants,flavors, flavors,glidants, glidants,lubricants, lubricants, preservatives, sorbents, preservatives, sorbents, and andvehicles. vehicles.Examples Examples of carriers, of carriers, adjuvants, adjuvants, and diluents and diluents include, include, but but are not are limited to, not limited to, ion ion exchangers, alumina, exchangers, alumina, aluminum aluminum stearate, stearate, lecithin, lecithin, serum serum proteins, proteins, such such as as humanserum human serum albumin, albumin, buffer buffer substances substances such such as as phosphates, phosphates, glycine,glycine, sorbic sorbic acid, acid, potassium potassium

sorbate, partial sorbate, partial glyceride mixturesofofsaturated glyceride mixtures saturatedvegetable vegetable fatty fatty acids,water, acids, water, saltsororelectrolytes, salts electrolytes, such as such as protamine protaminesulfate, sulfate,disodium disodium hydrogen hydrogen phosphate, phosphate, potassium potassium hydrogenhydrogen phosphate,phosphate,

sodiumchloride, sodium chloride,zinc zincsalts, salts,colloidal colloidalsilica, silica, magnesium magnesium trisilicate,polyvinyl trisilicate, polyvinyl pyrrolidone, pyrrolidone,

cellulose-basedsubstances, cellulose-based substances,polyethylene polyethylene glycol, glycol, sodium sodium carboxymethylcellulose, carboxymethylcellulose, polyacrylates, polyacrylates,

waxes,polyethylene-polyoxypropylene-block waxes, polyethylene-polyoxypropylene-block polymers, polymers, polyethylene polyethylene glycol andglycol and wool fat. wool fat.

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A "pharmaceutically

[0298] A "pharmaceutically

[0298] acceptable acceptable derivative" means any means derivative" non-toxic non-toxic anysalt, salt ester, ester, salt, of an salt of an 2023206094 18 Jul 2023

ester or ester or other other derivative of aa compound derivative of compound of this of this invention invention that, that, upon upon administration administration to a recipient, to a recipient,

is capable is of providing, capable of providing, either either directly directly oror indirectly, indirectly, aa compound compound of this of this invention invention or or an an inhibitorily active inhibitorily active metabolite orresidue metabolite or residuethereof. thereof.

[0299] As used

[0299] used herein, As herein, the term active active term "inhibitorily the"inhibitorily metabolite metabolite or residue thereof" thereof' or residue means means that aa metabolite that or residue metabolite or residuethereof thereofisisalso also ananinhibitor inhibitorofofACC. ACC. In some In some embodiments, embodiments, the the inhibitorily active inhibitorily active metabolite orresidue metabolite or residuethereof thereofisisselected selectedfrom from thefollowing: the following:

OH OH O O O O O OH OH O N OH N COH

/ N S N OH N S N O N S N N N O O O 0 HO HO 0 O

M+glucuronide M+glucuronide M-CH3. M-CH.

[0300] In some

[0300] In some embodiments, embodiments, the present the present invention invention provides provides a metaboliteofofCompound a metabolite Compound1, 1, wherein the wherein the metabolite metabolite isisthe M+glucuronide the M+glucuronideconjugate. conjugate.The The M+glucuronide conjugate has M+glucuronide conjugate has an an

IC50 ACC1 of of at ACCl ICo at 5 nM. 5 nM. In some In some embodiments, embodiments, the present inventioninvention the present provides provides a a metabolite metabolite of of Compound Compound 1, 1,wherein whereinthe themetabolite metabolite is is aa M-CH3demethylated metabolite.The M-CH demethylated metabolite. The M-CH3 M-CH

metabolite of metabolite of Compound Compound 1 1has has an anIC5o IC50 at at ACCl 22 nM. of22 ACCI of nM. InInsome someembodiments, embodiments,a provided a provided metaboliteofofCompound metabolite Compound1 is 1isolated. is isolated.

[0301] Compositions

[0301] Compositions of the present of the present invention invention may be administered may be administered orally, parenterally, orally, parenterally, by by inhalation spray, inhalation spray, topically, topically, rectally, rectally, nasally, nasally, buccally, vaginallyororvia buccally, vaginally viaananimplanted implanted reservoir. reservoir.

Theterm The term"parenteral" "parenteral"as as used used herein herein includes includes subcutaneous, subcutaneous, intravenous, intravenous, intramuscular, intramuscular, intra- intra articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial

injection or injection or infusion infusion techniques. techniques.Preferably, Preferably, thethe compositions compositions are administered are administered orally, orally,

intraperitoneally or intraperitoneally or intravenously. intravenously.Sterile Sterileinjectable injectableforms forms of of thethe compositions compositions of this of this invention invention

maybe may be aqueous aqueous oror oleaginous oleaginous suspension. suspension. These These suspensions suspensions may maybe beformulated formulated according according to to techniquesknown techniques known in the in the artart using using suitable suitable dispersing dispersing or wetting or wetting agents agents and suspending and suspending agents. agents.

Thesterile The sterile injectable injectable preparation preparationmay may also also be be a sterileinjectable a sterile injectablesolution solutionor or suspension suspension in ainnon- a non toxic parenterally toxic parenterally acceptable acceptablediluent diluentororsolvent, solvent,forforexample example as aassolution a solution in 1,3-butanediol. in 1,3-butanediol.

Among Among thethe acceptable acceptable vehicles vehicles and solvents and solvents thatbemay that may be employed employed areRinger's are water, water, Ringer's solution solution and isotonic and isotonic sodium sodium chloride chloride solution. solution. In addition, In addition, sterile, sterile, fixed fixed oilsareare oils conventionally conventionally

employedasas aa solvent employed solvent or orsuspending suspending medium. medium.

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thisthis

[0302] For For

[0302] purpose,anyany purpose, bland fixedoil blandfixed be employed maybe oil may employedincluding mono-oror synthetic mono- includingsynthetic 2023206094 18 Jul 2023

di-glycerides. Fatty di-glycerides. Fattyacids, acids,such suchasasoleic oleicacid acidand and itsitsglyceride glyceridederivatives derivatives areare useful useful in in thethe

preparationofofinjectables, preparation injectables, asas are are natural natural pharmaceutically-acceptable pharmaceutically-acceptable oils, oils, suchsuch as olive as olive oil oil or or castor oil, castor oil, especially especially in in their theirpolyoxyethylated versions.These polyoxyethylated versions. These oil oil solutions solutions or suspensions or suspensions may may also contain also contain aa long-chain long-chainalcohol alcoholdiluent diluent or or dispersant, dispersant, such such as carboxymethyl as carboxymethyl cellulose cellulose or or similar dispersing similar dispersing agents agentsthat thatare arecommonly commonlyused used in formulation in the the formulation of pharmaceutically of pharmaceutically

acceptable dosage acceptable dosage forms forms including including emulsions emulsions and and suspensions. suspensions. Other Other commonly used commonly used

surfactants, such surfactants, such as as Tweens, Tweens,Spans Spans and and other other emulsifying emulsifying agentsagents or bioavailability or bioavailability enhancers enhancers

whichare which arecommonly commonlyused used in theinmanufacture the manufacture of pharmaceutically of pharmaceutically acceptable acceptable solid,orliquid, solid, liquid, or other dosage other dosageforms formsmaymay alsoalso be used be used for purposes for the the purposes of formulation. of formulation.

[0303] Pharmaceutically

[0303] Pharmaceutically acceptable acceptable compositions compositions of thisinvention of this inventionmay maybebeorally orally administeredininany administered anyorally orallyacceptable acceptable dosage dosage form form including, including, butlimited but not not limited to, capsules, to, capsules,

tablets, aqueous tablets, suspensions aqueous suspensions or or solutions. solutions. In the In the case case of tablets of tablets forfor oral oral use, use, carrierscommonly carriers commonly used include used includelactose lactoseand andcorn corn starch.Lubricating starch. Lubricating agents, agents, such such as magnesium as magnesium stearate, stearate, are alsoare also typically added. typically added. For Fororal oraladministration administration incapsule in a a capsule form, form, useful useful diluents diluents include include lactose lactose and and dried cornstarch. dried cornstarch. When When aqueous aqueous suspensions suspensions are required are required for oralfor oraltheuse, use, the active active ingredient ingredient is is combinedwith combined with emulsifying emulsifying and suspending and suspending agents.agents. If desired, If desired, certain certain sweetening, sweetening, flavoringflavoring or or coloring agents coloring agentsmay may also also be be added. added.

In some

[0304] In some

[0304] embodiments, embodiments, a pharmaceutically a pharmaceutically acceptable acceptable composition composition comprising comprising a form a form

of Compound of Compound 1 as1 described as described herein herein is administered is administered as a capsule. as a capsule. Inembodiments, In some some embodiments, a a pharmaceuticallyacceptable pharmaceutically acceptable composition composition comprising comprising a form a form of of Compound Compound 1 asherein 1 as described described herein is administered is asaatablet. administered as tablet.

[0305] Alternatively,

[0305] Alternatively,pharmaceutically pharmaceuticallyacceptable acceptablecompositions compositionsofofthis this invention invention may be may be

administeredininthe administered theform formof of suppositories suppositories for for rectal rectal administration. administration. These These can can be be prepared prepared by by mixingthe mixing theagent agentwith with a suitablenon-irritating a suitable non-irritatingexcipient excipient that that is is solidatatroom solid room temperature temperature but but liquid at liquid at rectal rectal temperature andtherefore temperature and thereforewill willmelt meltin inthetherectum rectum to to release release thethe drug. drug. SuchSuch

materials include materials includecocoa cocoabutter, butter,beeswax beeswax and and polyethylene polyethylene glycols. glycols.

[0306] Pharmaceutically

[0306] Pharmaceutically acceptable acceptable compositions compositions of thisinvention of this inventionmay alsobebeadministered mayalso administered topically, especially topically, whenthe especially when thetarget targetofoftreatment treatmentincludes includes areas areas or organs or organs readily readily accessible accessible by by topical application, topical includingdiseases application, including diseasesofofthe theeye, eye,the theskin, skin,ororthe thelower lowerintestinal intestinaltract. tract. Suitable Suitable topical formulations topical arereadily formulations are readilyprepared prepared forfor each each of these of these areas areas or organs. or organs.

[0307] Topical

[0307] Topical application for thefor application lower lower intestinal the intestinal tractbecan tract can be effected effected in a in a rectal rectal suppositoryformulation suppository formulation (see (see above) above) or ainsuitable or in a suitable enema enema formulation. formulation. Topically-transdermal Topically-transdermal

patchesmay patches may alsobebe also used. used.

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[0308] For For

[0308] topical topical applications, provided applications, providedpharmaceutically pharmaceutically acceptable acceptable compositions compositions may maybebe 2023206094 18 Jul 2023

formulatedinina asuitable formulated suitableointment ointment containing containing the the active active component component suspended suspended or dissolved or dissolved in one in one or more or carriers. Carriers more carriers. Carriersfor fortopical topicaladministration administrationof of compounds compounds of invention of this this invention include, include, but but are not are limited to, not limited to, mineral oil, liquid mineral oil, liquid petrolatum, whitepetrolatum, petrolatum, white petrolatum,propylene propylene glycol, glycol,

polyoxyethylene, polyoxypropylene polyoxyethylene, compound,emulsifying polyoxypropylene compound, emulsifyingwax wax andand water.Alternatively, water. Alternatively, providedpharmaceutically provided pharmaceutically acceptable acceptable compositions compositions can be can be formulated formulated in a suitable in a suitable lotion orlotion or creamcontaining cream containingthethe active active components components suspended suspended or dissolved or dissolved in more in one or one or more pharmaceuticallyacceptable pharmaceutically acceptable carriers. carriers. Suitable Suitable carriers carriers include, include, but but are not are not limited limited to, mineral to, mineral

oil, sorbitan oil, sorbitan monostearate, polysorbate monostearate, polysorbate 60,60, cetyl cetyl esterswax, esters wax, cetearyl cetearyl alcohol, alcohol, 2-octyldodecanol, 2-octyldodecanol,

benzylalcohol benzyl alcoholand andwater. water.

[0309] For For

[0309] ophthalmic ophthalmic use,use, provided provided pharmaceutically pharmaceutically acceptable acceptable compositions compositions may may be be formulatedasasmicronized formulated micronized suspensions suspensions in isotonic, in isotonic, pH adjusted pH adjusted sterile sterile saline, saline, or, preferably, or, preferably, as as solutions in solutions in isotonic, isotonic, pH adjustedsterile pH adjusted sterilesaline, saline, either either with with oror without withouta apreservative preservativesuch such as as benzylalkonium benzylalkonium chloride. chloride. Alternatively, Alternatively, for ophthalmic for ophthalmic uses, uses, the pharmaceutically the pharmaceutically acceptable acceptable

compositionsmaymay compositions be formulated be formulated in an in an ointment ointment such assuch as petrolatum. petrolatum.

[0310] Pharmaceutically

[0310] Pharmaceutically acceptable acceptable compositions compositions of thisinvention of this inventionmay alsobebeadministered mayalso administered by nasal by nasal aerosol aerosolororinhalation. inhalation.Such Such compositions compositions are prepared are prepared according according to techniques to techniques well- well knownin inthetheartartofofpharmaceutical known pharmaceutical formulation formulation andbemay and may be prepared prepared as solutions as solutions in in saline, saline, employingbenzyl employing benzyl alcohol alcohol or other or other suitable suitable preservatives, preservatives, absorption absorption promoters promoters to enhance to enhance

bioavailability, fluorocarbons, bioavailability, fluorocarbons,and/or and/orother otherconventional conventional solubilizing solubilizing or dispersing or dispersing agents. agents.

[0311] MostMost

[0311] preferably, preferably, pharmaceutically pharmaceutically acceptable of of compositions acceptablecompositions thisinvention this are invention are formulatedfor formulated fororal oraladministration. administration.SuchSuch formulations formulations may may be be administered administered with or with or without without food. InInsome food. someembodiments, embodiments, pharmaceutically pharmaceutically acceptable acceptable compositions compositions of this invention of this invention are are administeredwithout administered without food. food. In other In other embodiments, embodiments, pharmaceutically pharmaceutically acceptable acceptable compositions compositions of of this invention this are administered invention are administeredwith with food. food.

[0312] The The

[0312] amount amount of compounds of compounds the present of theofpresent invention invention that be be maymay that combined withwith combined the the

carrier materials carrier to produce materials to produce a acomposition compositionin ainsingle a single dosage dosage form form will will vary vary depending depending upon upon the the host treated, host treated, the the particular particular mode mode ofofadministration. administration.Preferably, Preferably, provided provided compositions compositions should should be be formulatedsosothat formulated thata adosage dosageof of between between - 100- mg/kg 0.010.01 100 mg/kg body weight/day body weight/day of the inhibitor of the inhibitor can can be administered be administeredtotoa apatient patientreceiving receivingthese these compositions. compositions.

[0313] It should

[0313] It should alsounderstood also be be understood that a specific that a specific dosage dosage and treatment and treatment regimen regimen for any for any particular patient particular patient will will depend upon depend upon a variety a variety of of factors,including factors, including thethe activity activity of of thethe specific specific

compound compound employed, employed, the age, the age, body body weight, weight, generalgeneral health, health, sex,time sex, diet, diet,oftime of administration, administration, rate rate of excretion, of drugcombination, excretion, drug combination,andand the the judgment judgment oftreating of the the treating physician physician and and the the severity severity of of

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the particular the disease being particular disease beingtreated. treated. The The amount amount of aof a compound compound of the of the present present invention invention in the in the 2023206094 18 Jul 2023

compositionwill composition willalso alsodepend depend uponupon the particular the particular compound compound in the composition. in the composition.

[0314]

[0314] In embodiments, someembodiments, In some a crystalline formform a crystalline of Compound of Compound 1 is administered of a dose of at a dose at 1 is administered about 22 milligrams about milligramsto toabout about 500500 milligrams milligrams per day, per day, aboutabout 2 milligrams 2 milligrams to 400 to about about 400 milligrams milligrams

per day, per day, about about2 2milligrams milligramsto to about about 300300 milligrams milligrams per day, per day, about about 2 milligrams 2 milligrams to200 to about about 200 milligramsper milligrams perday, day,ororabout about 2 milligrams 2 milligrams to about to about 100 milligrams 100 milligrams perInday. per day. someIn some embodiments, embodiments, a crystalline a crystalline form form of Compound of Compound 1 is administered 1 is administered atofa dose at a dose about of about 5 milligrams 5 milligrams

per day, per day, about about6 6milligrams milligramsperper day, day, about about 7 milligrams 7 milligrams per day, per day, about about 8 milligrams 8 milligrams per per day, day, about 99 milligrams about milligramsperper day, day, about about 10 milligrams 10 milligrams per day, per day, aboutabout 11 milligrams 11 milligrams per day,per day,12about about 12 milligramsper milligrams perday, day,about about 13 13 milligrams milligrams per per day, day, aboutabout 14 milligrams 14 milligrams perabout per day, day,15about 15 milligramsper milligrams perday, day,1616milligrams milligrams per per day,day, 17 milligrams 17 milligrams per 18 per day, day, 18 milligrams milligrams per day,per 19 day, 19 milligramsper milligrams perday, day,2020 milligrams milligrams per per day,day, 21 milligrams 21 milligrams per 22 per day, day, 22 milligrams milligrams per day,per 23 day, 23 milligramsper milligrams perday, day,2424milligrams milligrams per per day,day, or milligrams or 25 25 milligrams per per day. day.

[0315]

[0315] In embodiments, someembodiments, In some a crystalline formform a crystalline of Compound of Compound 1 is administered of a dose of at a dose at 1 is administered greater than greater than about about5 5milligrams milligramsperper day, day, greater greater than than about about 10 milligrams 10 milligrams per greater per day, day, greater than than about 1515milligrams about milligramsperper day, day, greater greater than than about about 20 milligrams 20 milligrams per greater per day, day, greater than 25 than about about 25 milligramsper milligrams perday, day,greater greaterthan thanabout about 30 30 milligrams milligrams per day, per day, greater greater than than about about 35 milligrams 35 milligrams

per day, per day, greater greater than thanabout about4040milligrams milligrams per per day,day, greater greater thanthan about about 45 milligrams 45 milligrams perorday, per day, or greater than greater than about about5050milligrams milligramsperper day. day. In some In some embodiments, embodiments, a crystalline a crystalline form ofform of Compound Compound 1 is 1administered is administered at a at a dose dose of less of less than than aboutabout 300 milligrams 300 milligrams per day,per day, less less than than about about 275 milligrams 275 milligramsperper day, day, less less than than about about 250 250 milligrams milligrams per less per day, day, than less about than about 225 milligrams 225 milligrams

per day, per day, less less than than about about200 200milligrams milligrams perper day,day, lessless than than about about 175 milligrams 175 milligrams perless per day, day, less than about than about150 150milligrams milligrams perper day,day, lessless than than about about 125 milligrams 125 milligrams perless per day, day,than lessabout than 100 about 100 milligramsper milligrams perday. day.

[0316]

[0316] In someembodiments, In some embodiments,a crystalline formform a crystalline of Compound of Compound 1 is administered of a dose of at a dose at 1 is administered about 55 milligrams about milligramsonce once daily, daily, about about 20 milligrams 20 milligrams once once daily,daily, about about 30 milligrams 30 milligrams once once daily, daily, about 5050milligrams about milligrams once once daily, daily, about about 80 milligrams 80 milligrams once daily, once daily, about about 100 milligrams 100 milligrams once once daily, about daily, 150milligrams about 150 milligrams once once daily, daily, about about 200 200 milligrams milligrams once daily, once daily, about about 500 500 milligrams milligrams

once daily, once daily, about about800 800milligrams milligrams onceonce daily, daily, or about or about 1000 1000 milligrams milligrams once once daily. daily. In some

[0317] In some

[0317] embodiments, embodiments, a crystalline a crystalline form of of form Compound Compound is administered 1 is 1administered at a a doseofof at dose about 1010milligrams about milligrams twice twice daily, daily, about about 25 milligrams 25 milligrams twicetwice daily,daily, about about 50 milligrams 50 milligrams twice twice daily, or daily, or about 100milligrams about 100 milligrams twice twice daily. daily.

Pharmaceutical Uses Pharmaceutical Uses

[0318]

[0318] As usedherein, As used herein,the theterms terms"treatment," "treatment," "treat,"andand "treat," "treating" "treating" refer refer to to reversing, reversing,

alleviating, delaying alleviating, the onset delaying the onsetof, of, or or inhibiting inhibiting the the progress progressofofa adisease diseaseorordisorder, disorder,ororone oneoror

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more symptoms more symptomsthereof, thereof, as as described described herein. herein. In Insome some embodiments, treatment may embodiments, treatment be may be 2023206094 18 Jul 2023

administeredafter administered afterone oneorormore more symptoms symptoms have developed. have developed. In other In other embodiments, embodiments, treatment treatment maybe may be administered administered in in the the absence absence of ofsymptoms. For example, symptoms. For treatment may example, treatment be administered may be administered to aa susceptible to individual prior susceptible individual priortoto the the onset onsetofofsymptoms symptoms (e.g., (e.g., in in lightofof light a a historyofofsymptoms history symptoms and/or inin light and/or light of of genetic or other genetic or other susceptibility susceptibility factors). factors). Treatment Treatmentmaymay alsoalso be continued be continued after after

symptoms symptoms have have resolved, resolved, for for example example to prevent to prevent or their or delay delay recurrence. their recurrence.

[0319] The The

[0319] termterm "therapeutically "therapeutically effective amount"refers effectiveamount" an amount to an refers to amount of the compound of the as compound as

describedherein described hereinthat thatisis sufficient sufficient to to effect effect treatment treatment asas defined definedabove, above,when when administered administered to a to a patient (particularly patient (particularly aa human) human) ininneed need of of such such treatment treatment in one in one or more or more doses. doses. The The therapeutically effective therapeutically effective amount amount will will vary, vary, depending depending upon upon the patient, the patient, the disease the disease being being treated, treated,

the weight the and/orage weight and/or ageofofthethepatient, patient,the theseverity severityofofthe thedisease, disease,ororthe themanner manner of administration of administration

as determined as determined byby a qualifiedprescriber a qualified prescriber or or care care giver. giver.

Acetyl-CoA

[0320] Acetyl-CoA

[0320] carboxylase (ACC)(ACC) carboxylase catalyzes catalyzes the ATP-dependent the ATP-dependent carboxylation carboxylation of of acetyl-CoAto toform acetyl-CoA form malonyl-CoA. malonyl-CoA. This reaction, This reaction, which proceeds which proceeds in two half-reactions, in two half-reactions, a biotin a biotin carboxylase(BC) carboxylase (BC) reaction reaction andand a carboxyltransferase a carboxyltransferase (CT) reaction, (CT) reaction, is theisfirst the first committed committed step instep in fatty acid fatty acid (FA) biosynthesisand (FA) biosynthesis andis isthetherate-limiting rate-limitingreaction reactionforforthethepathway. pathway. In addition In addition to to its its role as role as aa substrate substrate in in FA biosynthesis,malonyl-CoA, FA biosynthesis, malonyl-CoA, the product the product of theofACC-catalyzed the ACC-catalyzed reaction,reaction,

also plays also an important plays an importantregulatory regulatory role role in in controlling controlling mitochondrial mitochondrial FA uptake FA uptake through through allosteric allosteric

inhibition of inhibition of carnitine carnitine palmitoyltransferase palmitoyltransferaseI I(CPT-I), (CPT-I),thethe enzyme enzyme catalyzing catalyzing the first the first committed committed

step in step in mitochondrial mitochondrial FAFA oxidation. oxidation. Malonyl-CoA, Malonyl-CoA, therefore, therefore, is a keyis metabolic a key metabolic signal signal for the for the control of control of FA FAproduction productionandand utilization utilization in in response response to dietary to dietary changes changes and altered and altered nutritional nutritional

requirementsininanimals, requirements animals,forforexample example during during exercise, exercise, and therefore and therefore plays plays a key a keyinrole role in controlling the controlling the switch switchbetween between carbohydrate carbohydrate andutilization and fat fat utilization in liver in liver and and skeletal skeletal muscle muscle

(Harwood, 2005). (Harwood, 2005). In mammals,

[0321] In mammals,

[0321] ACC exists ACC exists as two two tissue-specific as tissue-specific isozymes, isozymes, ACC ACC1 Iwhich which is present is present in in lipogenic tissues lipogenic tissues (liver, (liver, adipose) andACC2, adipose) and ACC2, which which is present is present in oxidative in oxidative tissues tissues (liver, (liver, heart, heart,

skeletal muscle). skeletal ACCl muscle). ACC1 and ACC2 and ACC2 are encoded are encoded by genes, by separate separate genes,distinct display displaycellular distinct cellular distributions, and distributions, share 75% and share 75% overall overall amino amino acidacid sequence sequence identity, identity, exceptexcept for anfor an extension extension at the at the N-terminus of ACC2 N-terminus of that direct ACC2 that direct ACC2 ACC2 toto the the mitochondrial mitochondrial membrane. ACC1,which membrane. ACC1, which lacksthis lacks this targeting sequence, targeting sequence,isislocalized localizedtotothe thecytoplasm. cytoplasm.In In thethe heart heart andand skeletal skeletal muscle, muscle, which which have have a a limited capacity limited capacitytoto synthesize synthesizefatty fattyacids, acids,the themalonyl-CoA malonyl-CoA formed formed byfunctions by ACC2 ACC2 functions to to regulate FA regulate FAoxidation. oxidation.In In thethe liver,thethemalonyl-CoA liver, malonyl-CoA formedformed in the in the cytoplasm cytoplasm through through the the actions of actions of ACC1 ACCisIis utilizedforforFAFA utilized synthesis synthesis and and elongation elongation leading leading to triglyceride to triglyceride formation formation

and VLDL and VLDL production,whereas production, whereasthe themalonyl-CoA malonyl-CoA formed formed at at thethe mitochondrialsurface mitochondrial surfaceby byACC2 ACC2 acts to acts to regulate FAoxidation regulate FA oxidation(Tong (Tong and and Harwood, Harwood, J. Cellular J. Cellular Biochem. Biochem. 99:2006). 99: 1476, 1476,This 2006). This

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compartmentalization compartmentalization of malonyl-CoA of malonyl-CoA resultsresults from a from a combination combination of synthesis of synthesis proximity proximity (Abu- (Abu 2023206094 18 Jul 2023

Elheigaetet al., Elheiga al., PNAS (USA) PNAS (USA) 102: 102: 12011, 12011, 2005) 2005) and theand theaction rapid rapid of action of malonyl-CoA malonyl-CoA

decarboxylase(Cheng decarboxylase (Cheng et al., et al., J. J. Med. Med. Chem. Chem. 49:1517, 49:1517, 2006).2006).

Simultaneous

[0322] Simultaneous

[0322] of of inhibition inhibition thethe enzymatic ACC1 Iand activities of ACC enzymaticactivities ACC2 and ACC2 offers the offersthe ability to ability to inhibit inhibitde de novo FAproduction novo FA productionin in lipogenic lipogenic tissues tissues (e.g.liver (e.g. liver& & adipose) adipose) while while at at the the sametime same timestimulating stimulating FA FA oxidation oxidation in oxidative in oxidative tissues tissues (e.g.(e.g. liverliver & skeletal & skeletal muscle) muscle) and and therefore offers therefore offers an an attractive attractive modality modalityfor forfavorably favorably affecting,in ina aconcerted affecting, concerted manner, manner, a a multitudeofofcardiovascular multitude cardiovascularrisk risk factorsassociated factors associated with with obesity, obesity, diabetes, diabetes, insulin insulin resistance, resistance, and and

the metabolic the metabolic syndrome. syndrome.

[0323] lines lines Several

[0323] Several of evidence of evidence strongly supportsupport strongly the concept of directof the concept direct inhibition inhibition of ACC of ACC activity as activity as an an important therapeutictarget important therapeutic targetfor fortreating treatingobesity, obesity,diabetes, diabetes,insulin insulinresistance, resistance,and and the metabolic the metabolic syndrome. syndrome.

[0324] Abu-Elheiga

[0324] Abu-Elheiga et al. et al. (Proc. (Proc. Nat.Acad. Natl. Acad.Sci. Sci. USA USA100:10207-10212, 100:10207-10212, 2003) 2003)

demonstratedthat demonstrated thatACC2 ACC2 knock-out knock-out mice exhibit mice exhibit reducedreduced skeletal skeletal and cardiac cardiacmalonyl- and muscle muscle malonyl CoA,increased CoA, increased muscle muscle FA oxidation, FA oxidation, reduced reduced hepatichepatic fat, reduced fat, reduced totalfat, total body body fat, elevated elevated

skeletal muscle skeletal uncoupling muscle uncoupling protein-3 protein-3 (UCP3) (UCP3) which which is indicative is indicative of increased of increased energy energy expenditure, reduced expenditure, reduced body body weight, weight, reduced reduced plasma plasma freereduced free FAs, FAs, reduced plasma and plasma glucose, glucose, and reducedtissue reduced tissueglycogen, glycogen,andand areare protected protected fromfrom diet-induced diet-induced diabetes diabetes and obesity. and obesity.

[0325] Savage

[0325] Savage et al.(J. et al. (J. Clin. Invest.116: Clin. Invest. 116:817, 817,2006), using 2006), ACC using ACC1 andACC2 Iand antisense ACC2 antisense

oligonucleotides,demonstrated oligonucleotides, demonstrated stimulation stimulation of FAofoxidation FA oxidation in isolated in isolated rat hepatocytes rat hepatocytes and in and in rats fed rats fed high-fat high-fat diets, diets, and and lowering lowering ofofhepatic hepatictriglycerides, triglycerides,improvements improvements in insulin in insulin sensitivity, sensitivity,

reductionsininhepatic reductions hepaticglucose glucoseproduction, production, and and increases increases in UCP1 in UCP1 mRNA mRNA in in highrats. high fat-fed fat-fed rats. These effects These effects were were greater greaterwhen whenboth bothACC ACC1Iand ACC2expression and ACC2 expressionwere weresuppressed suppressedthan thanwhen when either ACCl either or ACC2 ACC1 or ACC2expression expressionalone alonewas wassuppressed. suppressed.

[0326] Harwood

[0326] Harwood et (J. et al. al. (J.Biol. Biol.Chem. Chem.278: 278:37099, 37099,2003) 2003)demonstrated demonstratedthat thatthe the isozyme- isozyme nonselective ACC nonselective inhibitor, CP-640186, ACC inhibitor, CP-640186, which equally inhibits which equally inhibitsACC ACC1Iand and ACC2(IC = ACC2 (IC =50~60 60 nM)isolated nM) isolatedfrom from rat,mouse, rat, mouse, monkey monkey and human and human without without inhibiting inhibiting either either pyruvate pyruvate carboxylaseororpropionyl-CoA carboxylase propionyl-CoA carboxylase, carboxylase, reduced reduced FA synthesis, FA synthesis, triglyceride triglyceride synthesissynthesis and and secretion in secretion in Hep-G2 Hep-G2 cellswithout cells without affecting affecting cholesterol cholesterol synthesis, synthesis, and and reduced reduced apoB secretion apoB secretion

withoutaffecting without affectingapoAl apoAl secretion. secretion. CP-640186 CP-640186 also stimulated also stimulated FA oxidation FA oxidation in C2C12 in C2C12 cells and cells and in rat in rat muscle slices and muscle slices and increased increasedCPT-I CPT-I activity activity in in Hep-G2 Hep-G2 cells. cells. In experimental In experimental animals, animals, CP- CP 640186acutely 640186 acutely reduced reduced malonyl-CoA malonyl-CoA concentration concentration in both lipogenic in both lipogenic and oxidative and oxidative tissues in tissues in both the both the fed fed and andfasted fastedstate, state, reduced reducedliver liverand andadipose adipose tissue tissue FA FA synthesis, synthesis, and and increased increased whole whole

bodyFAFA body oxidation. oxidation. In In sucrose-fed sucrose-fed ratsrats treated treated with with CP-640186 CP-640186 for weeks, for three three weeks, CP-640186 CP-640186

time- and time- anddose-dependently dose-dependently reduced reduced liver, liver, muscle muscle and adipose and adipose triglycerides, triglycerides, reducedreduced body body

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weightdue weight duetotoselective selectivefat fatreduction reductionwithout without reducing reducing leanlean bodybody mass,mass, reduced reduced leptin leptin levels,levels, 2023206094 18 Jul 2023

reducedthe reduced thehyperinsulinemia hyperinsulinemia produced produced by theby the sucrose high high sucrose diet without diet without changingchanging plasma plasma glucoselevels, glucose levels, and andimproved improved insulin insulin sensitivity. sensitivity.

[0327] Saha et

[0327] Saha al.et(Diabetes al. (Diabetes 55:A288, 55:A288, 2006) demonstrated 2006) demonstrated stimulation stimulation of insulin of insulin sensitivity sensitivity in insulin-resistant in insulin-resistant rat rat muscle tissue by muscle tissue by CP-640186 CP-640186 within within 30 of 30 min mincompound of compound administration, administration,

and studies and studies bybyFurler Furleretetal. al. (Diabetes (Diabetes 55:A333, 55:A333, 2006) 2006) used used dual dual tracer tracer analysis analysis to show to show that that acute (46 acute (46 min) min)treatment treatmentof of ratswith rats withCP-640186 CP-640186 stimulated stimulated FA clearance FA clearance without without decreasing decreasing

glucoseclearance. glucose clearance.

[0328] ACC isACC

[0328] is the rate-limiting the rate-limiting enzyme enzyme in fatty in fatty acid acid synthesis synthesis and its product, and its product, malonyl malonyl CoA,serves CoA, servesasasananimportant important regulator regulator of fatty of fatty acid acid oxidation. oxidation. Hence, Hence, ACC inhibitors ACC inhibitors both both reducededenovo reduce novolipid lipidsynthesis synthesisandand promote promote the oxidation the oxidation of existing of existing fat. dual fat. This This effect dual effect on on lipid metabolism lipid raisesthe metabolism raises thepossibility possibilitythat thatACC ACC inhibitors inhibitors willwill be substantially be substantially moremore effective effective in in reducingexcess reducing excessfatfatthan thanother othermechanisms. mechanisms. Furthermore, Furthermore, ACC inhibitors ACC inhibitors willinsulin will impact impact insulin sensitivity, plasma sensitivity, andtissue plasma and tissuetriglycerides, triglycerides, and andfasting fastingplasma plasma glucose glucose as aasconsequence a consequence of of whole-body whole-body andand tissue-specific tissue-specific fat fat mass mass reduction reduction without without the for the need needpoly-pharmacy. for poly-pharmacy.

[0329] For the

[0329] Fortreatment the treatment of obesity of obesity andmetabolic and other other metabolic disorders, disorders, ACC inhibitors ACC inhibitors need only need only access the access the liver liver and andmuscle musclein inthetheperipheral peripheralcompartment. compartment. For oncological For oncological indications, indications, tumor tumor penetrationisis also penetration also required. required. However, However, avoiding avoiding the will the CNS CNSaddress will address many of many of side side effects effects associated with associated withthe thelate-stage late-stageobesity obesityprograms programs targeting targeting CNS CNS receptors. receptors. ACC inhibitors ACC inhibitors are are also expected also expectedtotohave havesuperior superior safety safety profilesto toexisting profiles existingmetabolic metabolic disease disease agents. agents. For example, For example,

it isisunlikely it unlikely that thatan anACC inhibitorwill ACC inhibitor willprecipitate precipitatelife-threatening life-threateninghypoglycemia hypoglycemia asoften as is is often seen with seen withinsulin insulinmimetics, mimetics,insulin insulinsecretagogues, secretagogues, and and insulin insulin degradation degradation inhibitors. inhibitors. Also,Also, since since ACC ACC inhibitorswill inhibitors will reduce reduce whole-body whole-body fat mass, fat mass, theybewill they will be superior superior to the to the glitazones glitazones that that increase whole-body increase whole-body fat fat mass mass as part as part of their of their mechanism mechanism of action. of action.

[0330] acting acting A peripherally

[0330] A peripherally agent that that causes agentcauses significant significant weight loss and loss weight and improves improves other other metabolicendpoints metabolic endpoints fitswell fits wellwithin within thethe U.S. U.S. FDA's FDA's requirements requirements for approval for approval of a newof a new obesity obesity agent. However, agent. However, if an if an approval approval for for obesity obesity continues continues to betochallenging be challenging in 5-7in 5-7 years, years, ACC ACC inhibitors could inhibitors could bebeapproved approvedforfor familialcombined familial combined hyperlipidemia hyperlipidemia and non-alcoholic and non-alcoholic

steatohepatitis (NASH). steatohepatitis (NASH).There There are currently are currently no marketed no marketed ACC inhibitors, ACC inhibitors, so an so an isozyme- isozyme nonselectiveACC nonselective ACC inhibitor inhibitor would would represent represent first-in-class first-in-class therapy therapy for treating for treating obesity obesity and and metabolicsyndrome, metabolic syndrome, in addition in addition to other to other disorders disorders mediated mediated by ACCby ACC enzymes. enzymes.

[0331] The The

[0331] activity activity of of a a providedcompound provided compound as an as an inhibitorofofACC inhibitor ACCor or treatmentfor treatment for obesity obesity or metabolic or syndrome, metabolic syndrome, maymay be assayed be assayed in vitro in vitro or in or in vivo. vivo. An in An vivoinassessment vivo assessment of the of the efficacy of efficacy of the the compounds compounds of the of the invention invention may may be be using made madeanusing an model animal animal of model obesityof orobesity or metabolicsyndrome, metabolic syndrome, e.g., e.g., a rodent a rodent or primate or primate model. model. Cell-based Cell-based assays assays may be performed may be performed

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using, e.g., using, e.g., aa cell cellline lineisolated isolatedfrom from aa tissue tissue that thatexpresses expresses ACC. Additionally, ACC. Additionally, biochemical biochemical or or 2023206094 18 Jul 2023

mechanism-based mechanism-based assays, assays, e.g.,e.g., transcription transcription assays assays usingusing a purified a purified protein, protein, Northern Northern blot, blot, RT- RT PCR,etc., PCR, etc., may maybebeperformed. performed. In vitro In vitro assays assays include include assaysassays that determine that determine cell morphology, cell morphology,

protein expression, protein expression,and/or and/orthethecytotoxicity, cytotoxicity,enzyme enzyme inhibitory inhibitory activity, activity, and/or and/or the subsequent the subsequent

functional consequences functional consequencesof of treatment treatment of cells of cells withwith compounds compounds of the of the invention. invention. Alternate Alternate in in vitro assays vitro quantitate the assays quantitate the ability ability of of the the inhibitor inhibitor to to bind to protein bind to or nucleic protein or nucleic acid acid molecules molecules within the within the cell. cell. Inhibitor Inhibitor binding bindingmay maybe be measured measured by radiolabeling by radiolabeling the inhibitor the inhibitor prior prior to to binding, isolating binding, isolating the the inhibitor/target inhibitor/target molecule moleculecomplex complex and and determining determining the amount the amount of of radiolabel bound. radiolabel bound.Alternatively, Alternatively, inhibitor inhibitor binding binding may may be determined be determined by running by running a competition a competition

experimentwhere experiment where new new inhibitors inhibitors are incubated are incubated with purified with purified proteins proteins or nucleic or nucleic acids tobound acids bound to known known radioligands. radioligands. Detailed Detailed conditions conditions for assaying for assaying a compound a compound utilized utilized in this invention in this invention as as an inhibitor an inhibitor of of ACC ACC areare setset forthininthe forth theExamples Examples below. below. The aforementioned The aforementioned assays assays are are exemplaryandand exemplary notnot intended intended to limit to limit the the scope scope of the of the invention. invention. The skilled The skilled practitioner practitioner can can appreciate that appreciate that modifications modificationscancan be be made made to conventional to conventional assaysassays to develop to develop equivalent equivalent assays assays that obtain that the same obtain the sameresult. result.

[0332]

[0332]

[0333] A provided

[0333] A provided compound compound or composition or composition thereof thereof mayadministered may be usingusing be administered any amount any amount

and any and anyroute routeofofadministration administration effective effective forfor treatingor or treating lessening lessening thethe severity severity of of a metabolic a metabolic

disorder or disorder or condition, condition,cancer, cancer,a abacterial bacterialinfection, infection,aafungal fungalinfection, infection,a aparasitic parasitic infection infection(e.g. (e.g. malaria), an malaria), an autoimmune autoimmune disorder, disorder, a neurodegenerative a neurodegenerative or neurological or neurological disorder, disorder, schizophrenia, schizophrenia,

a bone-related a disorder,liver bone-related disorder, liverdisease, disease, ororaa cardiac cardiacdisorder. disorder.

[0334] In some

[0334] In some embodiments, embodiments, a provided a provided compound compound or composition or composition thereof thereof may may be be administeredusing administered using any any amount amount androute and any any route of administration of administration effective effective for treating for treating or or lessening the lessening the severity severity ofofaa disease diseaseassociated associatedwith with ACC ACC (Tong(Tong et al.et"Acetyl-coenzyme al. "Acetyl-coenzyme A A carboxylase:crucial carboxylase: crucialmetabolic metabolic enzyme enzyme and attractive and attractive target target for drug for drug discovery" discovery" Cell Cell and and MolecularLife Molecular LifeSciences Sciences (2005) (2005) 62, 62, 1784-1803). 1784-1803).

[0335] In some

[0335] In some embodiments, embodiments, a provided a provided compound compound or composition or composition thereof thereof may may be be administeredusing administered using any any amount amount androute and any any route of administration of administration effective effective for treating for treating or or lessening the lessening the severity severityofofaa metabolic metabolicdisorder, disorder,disease, disease,or or condition. condition. In some In some embodiments, embodiments, the the metabolicdisorder metabolic disorderisisobesity, obesity,metabolic metabolic syndrome, syndrome, diabetes diabetes or diabetes-related or diabetes-related disorders disorders

including Type including Type1 diabetes 1 diabetes (insulin-dependent (insulin-dependent diabetes diabetes mellitus, mellitus, IDDM)IDDM) and Typeand Type 2 2 diabetes diabetes (non-insulin-dependent (non-insulin-dependent diabetes diabetes mellitus, mellitus, NIDDM), NIDDM), impaired impaired glucose glucose tolerance, tolerance, insulin insulin resistance, hyperglycemia, resistance, hyperglycemia,diabetic diabetic complications, complications, including, including, but limited but not not limited to atherosclerosis, to atherosclerosis,

coronaryheart coronary heartdisease, disease,stroke, stroke,peripheral peripheralvascular vascular disease, disease, nephropathy, nephropathy, hypertension, hypertension,

neuropathyandand neuropathy nephropathy; nephropathy; obesity obesity comorbidities comorbidities including including but notbut not limited limited to metabolic to metabolic

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syndrome,dyslipidemia, syndrome, dyslipidemia, hypertension, hypertension, insulin insulin resistance, resistance, diabetes diabetes (including (including Type 1Type 1 and and Type 2 Type 2 2023206094 18 Jul 2023

diabetes), coronary diabetes), coronaryartery arterydisease, disease,and andheart heartfailure. failure.InInsome some embodiments, embodiments, the metabolic the metabolic

disorder, disease disorder, disease or or condition conditionisisnon-alcoholic non-alcoholicfatty fattyliver liverdisease diseaseororhepatic hepaticinsulin insulin resistance.In resistance. In someembodiments, some embodiments, the metabolic the metabolic disorder disorder is non-alcoholic is non-alcoholic steatohepatitis. steatohepatitis.

Combination Therapy Combination Therapy

[0336] In some

[0336] In some embodiments, embodiments, the present the present invention invention provides provides a method a method of of treatingaa treating

metabolicdisorder, metabolic disorder,disease, disease,ororcondition conditiondescribed described herein, herein, comprising comprising administering administering a a compound compound of the of the invention invention in conjunction in conjunction with with one orone orpharmaceutical more more pharmaceutical agents. agents. Suitable Suitable pharmaceuticalagents pharmaceutical agents that that maymay be used be used in combination in combination with with the the compounds compounds of the of the present present invention include invention includeanti-obesity anti-obesityagents agents (including (including appetite appetite suppressants), suppressants), anti-diabetic anti-diabetic agents, agents, anti-anti

hyperglycemic hyperglycemic agents, agents, lipid lipid lowering lowering agents, agents, and and anti-hypertensive anti-hypertensive agents. agents.

[0337] lipid lipid Suitable

[0337] Suitable agents agents lowering lowering that can be can that in used usedbe in conjunction conjunction with a with a provided provided compound compound or or composition composition thereof thereof include include butnotarelimited but are not limited to, acid to, bile bile sequestrants, acid sequestrants, HMG- HMG CoAreductase CoA reductase inhibitors,HMG-CoA inhibitors, HMG-CoA synthasesynthase inhibitors, inhibitors, cholesterol cholesterol absorption absorption inhibitors, inhibitors, acyl acyl coenzyme coenzyme A-cholesterol A-cholesterol acylacyl transferase transferase (ACAT) (ACAT) inhibitors, inhibitors, CETP inhibitors, CETP inhibitors, squalene squalene synthetase inhibitors, synthetase inhibitors, PPAR-alpha PPAR-alpha agonists, agonists, FXR FXR receptor receptor modulators, modulators, LXR LXR receptor receptor modulators,lipoprotein modulators, lipoproteinsynthesis synthesis inhibitors,renin-angiotensin inhibitors, renin-angiotensin system system inhibitors, inhibitors, PPAR-delta PPAR-delta

partial agonists, partial agonists, bile bile acid acid reabsorption inhibitors, PPAR-gamma reabsorption inhibitors, PPAR-gamma agonists, agonists, triglyceride triglyceride synthesis synthesis

inhibitors, microsomal inhibitors, triglyceridetransport microsomal triglyceride transport inhibitors,transcription inhibitors, transcriptionmodulators, modulators, squalene squalene

epoxidaseinhibitors, epoxidase inhibitors,low lowdensity densitylipoprotein lipoprotein receptor receptor inducers, inducers, platelet platelet aggregation aggregation inhibitors, inhibitors,

5-LOororFLAP 5-LO FLAP inhibitors, inhibitors, niacin, niacin, and and niacin-bound niacin-bound chromium. chromium.

Suitable

[0338] Suitable

[0338] anti-hypertensive anti-hypertensive that canthat agents agents can be be used in used in conjunction conjunction with a with a provided provided compound compound or composition or composition thereof thereof include include butnotarelimited but are not limited to diuretics, to diuretics, beta-adrenergic beta-adrenergic

blockers, calcium blockers, calciumchannel channel blockers, blockers, angiotensin angiotensin converting converting enzymeenzyme (ACE) inhibitors, (ACE) inhibitors, neutral neutral endopeptidaseinhibitors, endopeptidase inhibitors,endothelin endothelin antagonists, antagonists, vasodilators, vasodilators, angiotensin angiotensin II receptor II receptor

antagonists, alpha/beta antagonists, alpha/betaadrenergic adrenergicblockers, blockers, alpha alpha 1 blockers, 1 blockers, alpha alpha 2 agonists, 2 agonists, aldosterone aldosterone

inhibitors, mineralocorticoid inhibitors, receptorinhibitors, mineralocorticoid receptor inhibitors,renin renininhibitors, inhibitors,and andangiopoietin angiopoietin 2 binding 2 binding

agents. agents.

[0339] Suitable

[0339] Suitable anti-diabetic agentsagents anti-diabetic thatbecan that can beinused used in conjunction conjunction with a with a provided provided compound compound or or composition composition thereof thereof include include butnotarelimited but are not limited to acetyl-CoA to other other acetyl-CoA carboxylase carboxylase

(ACC)inhibitors, (ACC) inhibitors, DGAT-1 inhibitors, AZD7687, DGAT-1 inhibitors, LCQ908, AZD7687, LCQ908, DGAT-2 DGAT-2 inhibitors, inhibitors,

monoacylglycerol monoacylglycerol 0-acyltransferase O-acyltransferase inhibitors, inhibitors, PDE-10 PDE-10 inhibitors, inhibitors, AMPK activators, AMPK activators,

sulfonylureas(e.g. sulfonylureas (e.g. acetohexamide, acetohexamide, chlorpropamide, chlorpropamide, diabinese, diabinese, glibenclamide, glibenclamide, glipizide, glipizide,

glyburide, blimipiride, glyburide, blimipiride,gliclazide, gliclazide, glipentide, glipentide, gliquidone, gliquidone,glisolamide, glisolamide, tolazamide, tolazamide, tolbutamide), tolbutamide),

meglitinides, alpha-amylase meglitinides, alpha-amylase inhibitors inhibitors (e.g. (e.g. tendamistat, tendamistat, treastatin,AL-3688), treastatin, AL-3688), alpha-glucoside alpha-glucoside

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hydrolaseinhibitors hydrolase inhibitors(e.g. (e.g. acarbose), acarbose),alpha-glucosidase alpha-glucosidase inhibitors inhibitors (e.g. (e.g. adiposine, adiposine, camiglibose, camiglibose, 2023206094 18 Jul 2023

emiglitate, miglitol, emiglitate, miglitol, voglibose, pradimicin-Q, voglibose, pradimicin-Q, sarbostatin), sarbostatin), PPAR-gamma PPAR-gamma agonistsagonists (e.g. (e.g. balaglitazone, ciglitazone, balaglitazone, ciglitazone, darglitazone, darglitazone,englitazone, englitazone,isaglitazone, isaglitazone,pioglitazone, pioglitazone, rosiglitazone, rosiglitazone,

troglitazone), PPAR-alpha/gamma troglitazone), agonists (e.g. PPAR-alpha/gamma agonists (e.g. CLX-0940, GW-1536,GW-1929, CLX-0940, GW-1536, GW-1929, GW-2433, GW-2433,

KRP-297,L-796449, KRP-297, L-796449,LR-90, LR-90,MK-0767, MK-0767, SB-219994), SB-219994), biguanides biguanides (e.g. (e.g. metformin, metformin, buformin), buformin),

GLP-1modulators GLP-1 modulators (exendin-3, (exendin-3, exendin-4), exendin-4), liraglutide, liraglutide, albiglutide, albiglutide, exenatide exenatide (Byetta), (Byetta),

taspoglutide, lixisenatide, taspoglutide, lixisenatide, dulaglutide, dulaglutide, semaglutide, semaglutide,N,N-9924, N,N-9924, TTP-054, TTP-054, PTP-1B PTP-1B inhibitors inhibitors

(trodusquemine,hyrtiosal (trodusquemine, hyrtiosal extract),SIRT-1 extract), SIRT-1 inhibitors inhibitors (e.g. (e.g. resveratrol, resveratrol, GSK2245840, GSK2245840,

GSK184072), GSK184072), DPP-IV DPP-IV inhibitors inhibitors (e.g. sitagliptin, (e.g. sitagliptin, vildagliptin, vildagliptin, alogliptin, alogliptin, dutogliptin, dutogliptin, linagliptin, linagliptin,

saxagliptin), insulin saxagliptin), insulin secretagogues, secretagogues,fatty fattyacid acidoxidation oxidationinhibitors, inhibitors,A2A2 antagonists, antagonists, JNK JNK

inhibitors, glucokinase inhibitors, activators glucokinase (e.g.(e.g. activators TTP-399, TTP-355, TTP-399, TTP-547, TTP-355, AZD1656, TTP-547, AZD1656, ARRY403, ARRY403,

MK-0599,TAK-329, MK-0599, TAK-329, AZD5658, AZD5658, GKM-001), GKM-001), insulin, insulin, insulin insulin mimetics, mimetics, glycogen glycogen phosphorylase phosphorylase

inhibitors (e.g. inhibitors (e.g. GSK1362885), VPAC2 GSK1362885), VPAC2 receptor receptor agonists, agonists, SGLT2 inhibitors SGLT2 inhibitors (dapagliflozin, (dapagliflozin,

canagliflozin, BI-10733, canagliflozin, BI-10733,tofogliflozin, ASP-1941, tofogliflozin, THR1474, ASP-1941, THR1474, TS-071, TS-071, ISIS388626, ISIS388626, LX4211), LX4211),

glucagon receptor glucagon receptor modulators, modulators, GPR119 modulators(e.g. GPR119 modulators (e.g. MBX-2982, GSK1292263, MBX-2982, GSK1292263, APD597, APD597,

PSN821), FGF21 PSN821), FGF21 derivatives, TGR5 derivatives, TGR5 (GPBAR1) (GPBAR1) receptor receptor agonists agonists (e.g.INT777), (e.g. INT777),GPR40 GPR40 agonists (e.g. agonists (e.g. TAK-875), GPR120 TAK-875), GPR120 agonists, agonists, nicotinic nicotinic acid receptor acid receptor (HM74A)(HM74A) activators, activators, SGLT1 SGLT1 inhibitors (e.g. inhibitors (e.g. GSK1614235), carnitine GSK1614235), carnitine palmitoyl palmitoyl transferase transferase enzyme enzyme inhibitors, inhibitors, fructose fructose 1,6- 1,6 diphosphataseinhibitors, diphosphatase inhibitors,aldose aldosereductase reductase inhibitors, inhibitors, mineralocorticoid mineralocorticoid receptor receptor inhibitors, inhibitors,

TORC2 TORC2 inhibitors, CCR2 inhibitors, CCR2inhibitors, inhibitors, CCR5 inhibitors, PKC CCR5 inhibitors, (e.g. PKC-alpha, PKC (e.g. PKC-beta, PKC- PKC-alpha, PKC-beta, PKC gamma) gamma) inhibitors,fatty inhibitors, fattyacid acidsynthetase synthetase inhibitors, inhibitors, serine serine palmitoyl palmitoyl transferase transferase inhibitors, inhibitors,

GPR81modulators, GPR81 modulators,GPR39 GPR39 modulators, modulators, GPR43 GPR43 modulators, modulators, GPR41 GPR41 modulators, modulators, GPR105 GPR105

modulators,Kv1.3 modulators, Kvl.3 inhibitors, inhibitors, retinolbinding retinol binding protein protein 4 inhibitors, 4 inhibitors, glucocorticoid glucocorticoid receptor receptor

modulators, somatostatin modulators, somatostatin receptor receptor(e.g. SSTR1, (e.g. SSTR1,SSTR2, SSTR2, SSTR3, SSTR5)inhibitors, SSTR3, SSTR5) inhibitors, PDHK2 PDHK2

inhibitors, PDHK4 inhibitors, inhibitors, MAP4K4 PDHK4 inhibitors, inhibitors, IL1-beta MAP4K4 inhibitors, IL1-beta modulators, modulators,and andRXR-alpha RXR-alpha

modulators. modulators.

[0340] Suitable

[0340] Suitable anti-obesity anti-obesity includeinclude agentsagents not are but arebut not limited limited to,11-beta-hydroxysteroid to, 11-beta-hydroxysteroid

dehydrogenase dehydrogenase 1 inhibitors, 1 inhibitors, stearoyl-CoA stearoyl-CoA desaturase desaturase (SCD-1) (SCD-1) inhibitors, inhibitors, MCR-4 MCR-4 agonists, agonists, CCK-A CCK-A agonists, agonists, monoamine monoamine reuptake reuptake inhibitors inhibitors (e.g. sibutramine), (e.g. sibutramine), sympathomimetic sympathomimetic agents, agents, beta-3-adrenergicreceptor beta-3-adrenergic receptoragonists, agonists,dopamine dopamine receptor receptor agonists agonists (e.g. (e.g. bromocriptine), bromocriptine),

melanocyte-stimulating melanocyte-stimulating hormone hormone and analogs and analogs thereof, thereof, 5-HT2c (e.g. 5-HTc agonists agonists (e.g. lorcaserin lorcaserin / Belviq),/ Belviq), melaninconcentrating melanin concentrating hormone hormone antagonists, antagonists, leptin, leptin, leptin leptin analogs, analogs, leptinleptin agonists, agonists, galanin galanin

antagonists, lipase antagonists, lipase inhibitors inhibitors (e.g. (e.g. tetrahydrolipstatin tetrahydrolipstatin // Orlistat), Orlistat), anorectic anorectic agents (e.g. bombesin agents (e.g. bombesin

agonists), NPY agonists), NPY antagonists antagonists (e.g.velneperit), (e.g. velneperit),PYY3-36 PYY3-36 (and(and analogs analogs thereof), thereof), BRS3 BRS3 modulators, modulators,

opioid receptor opioid receptormixed mixed antagonists, antagonists, thyromimetic thyromimetic agents, agents, dehydroepiandrosterone, dehydroepiandrosterone, glucocorticoid glucocorticoid

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agonists or agonists or antagonists, antagonists, orexin orexinantagonists, antagonists,GLP-1 GLP-1 agonists, agonists, ciliary ciliary neurotrophic neurotrophic factors factors (e.g.(e.g. 2023206094 18 Jul 2023

Axokine),human Axokine), human agouti-related agouti-related protein protein (AGRP) (AGRP) inhibitors, inhibitors, H3 antagonists H3 antagonists or agonists, or inverse inverse agonists, neuromedin neuromedin U agonists, U agonists, MTP/ApoB MTP/ApoB inhibitors inhibitors (e.g. gut-selective (e.g. gut-selective MTP inhibitors MTP inhibitors such as such as dirlotapide, JTT130, dirlotapide, Usistapide, JTT130, Usistapide, SLX4090), SLX4090), MetAp2MetAp2 inhibitors inhibitors (e.g. ZGN-433), (e.g. ZGN-433), agents agents with with mixedmodulatory mixed modulatory activity activity at two at two or more or more of glucagon, of glucagon, GIP, GIP, and andreceptors GLP1 GLP1 receptors (e.g. MAR-(e.g. MAR 701, ZP2929), 701, ZP2929),norepinephrine norepinephrine reuptake reuptake inhibitors, inhibitors, opioid opioid antagonists antagonists (e.g. naltrexone), (e.g. naltrexone), CB1 CB1 receptor antagonists receptor antagonistsororinverse inverseagonists, agonists,ghrelin ghrelinagonists agonists or or antagonists, antagonists, oxyntomodulin oxyntomodulin and and analogsthereof, analogs thereof, monoamine monoamine uptake uptake inhibitors inhibitors (e.g. (e.g. tesofensine), tesofensine), and combination and combination agents agents (e.g. (e.g. buproprionplus buproprion pluszonisamide zonisamide (Empatic), (Empatic), pramlintide pramlintide plus metreleptin, plus metreleptin, buproprion buproprion plus naltrexone plus naltrexone

(Contrave), phentermine (Contrave), phentermine plus plus topiramate topiramate (Qsymia). (Qsymia).

In some

[0341] In some

[0341] embodiments, embodiments, the anti-obesity the anti-obesity agents agents used in incombination used witha aprovided combinationwith provided compound compound or composition or composition thereof thereof are selected are selected from gut-selective from gut-selective MTP inhibitors MTP inhibitors (e.g. (e.g. dirlotapide, mitratapide, dirlotapide, implitapide,R56918), mitratapide, implitapide, R56918), CCK-A CCK-A agonists, agonists, 5-HT2c agonists 5-HTc agonists (e.g. lorcaserin (e.g. lorcaserin

// Belviq), Belviq), MCR4 agonists, MCR4 agonists, lipase lipase inhibitors inhibitors (e.g. (e.g. Cetilistat),PYY-36 Cetilistat), PYY3-36 (including (including analogs analogs and and PEGylated PEGylated analogs analogs thereof), thereof), opioid opioid antagonists antagonists (e.g.(e.g. naltrexone), naltrexone), oleoyl oleoyl estrone, estrone, obinepitide, obinepitide,

pramlintide, tesofensine, pramlintide, tesofensine,leptin, leptin, bromocriptine, bromocriptine,orlistat, orlistat,AOD-9604, AOD-9604, and sibutramine. and sibutramine.

In some

[0342] In some

[0342] embodiments, embodiments, a provided a provided compound compound or composition, or composition, according according to to the the methodofofthethepresent method presentinvention, invention, maymay be administered be administered using using any amount any amount and any and any route of route of administrationeffective administration effectivefor fortreating treatingororlessening lesseningthe theseverity severityofofa aLKB1 LKB1 or Kras or Kras associated associated

disease. InInsome disease. someembodiments, embodiments, the LKB1 the LKB1 or Kras or Kras associated associated disease disease is is selected selected from from hepatocellular carcinoma, hepatocellular carcinoma,LKB1 mutant cancers, LKB1 mutant cancers, LKB1 loss of LKB1 loss of heterozygosity heterozygosity (LOH) driven (LOH) driven

cancers, Kras cancers, Krasmutant mutant cancers, cancers, Peutz-Jeghers Peutz-Jeghers syndrome syndrome (PJS), (PJS), Cowden's Cowden's disease disease (CD), and (CD), and tubeous sclerosis tubeous sclerosis (TS) (TS)(Makowski (Makowski et et al. al."Role "Roleofof LKB1 LKB1 in inLung Lung Cancer Cancer Development" British Development" British

Journal of Journal of Cancer Cancer (2008) (2008) 99, 99,683-688). 683-688).In Insome some embodiments, the LKB1 embodiments, the or Kras LKB1 or Kras associated associated disease is disease is aa Kras positive/LKB1 Kras positive/LKB1 deficient deficient lunglung tumor. tumor.

In some

[0343] In some

[0343] embodiments, embodiments, a provided a provided compound compound or composition, or composition, according according to to the the methodofof method thepresent the present invention, invention, maymay be administered be administered using using any amount any amount and any and any route of route of administrationeffective administration effectivefor fortreating treatingororlessening lesseningthe theseverity severityofofa acancer, cancer,ororinhibiting inhibitingthethe growthofofororinducing growth inducing apoptosis apoptosis in cancer in cancer cells cells (Wang (Wang et"Acetyl-CoA et al. al. "Acetyl-CoA Carboxylase-alpha Carboxylase-alpha

Inhibitor TOFA Inhibitor Induces Human TOFA Induces Human Cancer Cancer CellApoptosis" Cell Apoptosis" Biochem Biochem Biophys Biophys Res Res Commun. Commun.

(2009) 385(3), (2009) 385(3),302-306; 302-306; Chajes Chajes et al. et al. "Acetyl-CoA "Acetyl-CoA Carboxylase Carboxylase alpha Isalpha Is Essential Essential to Breastto Breast CancerCell Cancer CellSurvival" Survival" Cancer Cancer Res.Res. (2006) (2006) 66, 5287-5294; 66, 5287-5294; Beckers Beckers et al. "Chemical et al. "Chemical InhibitionInhibition of of Acetyl-CoA Acetyl-CoA Carboxylase Carboxylase Induces Induces GrowthGrowth Arrest Arrest and and Cytotoxicity Cytotoxicity Selectivity Selectivity in Cancer in Cancer Cells" Cells" CancerRes. Cancer Res.(2007) (2007) 8180-8187; 8180-8187; Brusselmans Brusselmans et al. et al.Interference-Mediated "RNA "RNA Interference-Mediated Silencing ofSilencing the of the Acetyl-CoA-Carboxylase-alphaGene Acetyl-CoA-Carboxylase-alpha Gene Induces Induces Growth Growth Inhibitionand Inhibition andApoptosis ApoptosisofofProstate Prostate

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Cancer Cells" Cancer Cells" Cancer Cancer Res. Res. (2005) (2005) 65, 65, 6719-6725; 6719-6725; Brunet Brunet et etal. al."BRCA1 and Acetyl-CoA "BRCA1 and Acetyl-CoA 2023206094 18 Jul 2023

Carboxylase: The Carboxylase: Metabolic Syndrom The Metabolic SyndromofofBreast BreastCancer" Cancer"Molecular MolecularCarcinogenesis Carcinogenesis(2008) (2008)47, 47, 157-163;Cairns 157-163; Cairnsetetal. al."Regulation "Regulationof of Cancer Cancer CellCell Metabolism" Metabolism" (2011) (2011) 11, Chiaradonna 11, 85-95; 85-95; Chiaradonna et al. et al."From "From Cancer Cancer Metabolism to New Metabolism to Biomarkersand New Biomarkers andDrug DrugTargets" Targets"Biotechnology Biotechnology Advances(2012) Advances (2012)30, 30, 30-51). 30-51). In some

[0344] In some

[0344] embodiments, embodiments, a provided a provided compound compound or composition, or composition, according according to to the the methodofofthethepresent method presentinvention, invention, maymay be administered be administered using using any amount any amount and any and any route of route of administrationeffective administration effectivefor fortreating treatingororlessening lesseningthe theseverity severityofofa amelanoma. melanoma. In In some some embodiments, the embodiments, the melanoma melanomaisisone onebearing bearing an an activated activated MAPK pathway MAPK pathway (Pettietet al. (Petti al. "AMPK "AMPK

activators inhibit activators inhibit the the proliferation of human proliferation of melanomas human melanomas bearing bearing the activated the activated MAPK MAPK pathway" pathway" MelanomaResearch Melanoma Research(2012) (2012)22, 22,341-350). 341-350).

[0345] A provided

[0345] A provided compound compound findsutility finds special triple in specialinutility triple negative negative breastascancer, breast cancer, the as the tumorsuppressor tumor suppressor protein protein BRCA1 BRCA1 binds binds and stabilizes and stabilizes the inactive the inactive form of form ACC, of ACC, thus thus regulating regulating

de novo de novolipid lipidsynthesis. synthesis.Deletion Deletion or or mutation mutation of this of this tumor tumor suppressor suppressor protein protein results results in theinloss the loss of the of the binding andstabilization binding and stabilizationofofthe theinactive inactiveform formof of ACC, ACC, resulting resulting in increased in increased capacity capacity for for ACC-driven ACC-driven de de novonovo lipogenesis, lipogenesis, resulting resulting in cancer in cancer cell proliferation. cell proliferation. See Brunet See Brunet et al. et al. "BRCA1 "BRCA1 andand acetyl-CoA acetyl-CoA carboxylase:thethemetabolic carboxylase: metabolicsyndrome syndrome of of breastcancer" breast cancer" Mol. Mol. Carcinog. Carcinog. (2008) 47(2), (2008) 47(2),157-163. 157-163. In some

[0346] In some

[0346] embodiments, embodiments, a provided a provided compound compound or composition, or composition, according according to to the the methodofofthethepresent method presentinvention, invention, maymay be administered be administered using using any amount any amount and any and any route of route of administrationeffective administration effectivefor fortreating treatingororlessening lesseningthe theseverity severityofofa aliposarcoma. liposarcoma. Liposarcomas Liposarcomas

havebeen have beenshown shown to depend to depend on deon de long-chain novo novo long-chain fattysynthesis fatty acid acid synthesis for growth, for growth, and inhibition and inhibition

of ACC of ACC by by soraphen soraphen A inhibited A inhibited lipogenesis lipogenesis as as as well well as tumor tumor cell growth cell growth (Olsen (Olsen et et al. al. "Fatty "Fatty acid synthesis acid synthesis isis aa therapeutic therapeutic target target in in human human liposarcoma" liposarcoma" International International J. ofJ.Oncology of Oncology (2010) (2010)

36, 1309-1314). 36, 1309-1314).

In some

[0347] In some

[0347] embodiments, embodiments, a provided a provided compound compound or composition, or composition, according according to to the the methodofofthethepresent method presentinvention, invention, maymay be administered be administered using using any amount any amount and any and any route of route of administrationeffective administration effectivefor fortreating treatingororlessening lesseningthe theseverity severityofofa aliver liverdisease. disease.InInsome some embodiments, embodiments, thethe liver liver disease disease is is selected selected from from alcoholic alcoholic fatty fatty liver liver disease disease (AFLD), (AFLD), familial familial

combinedhyperlipidemia, combined hyperlipidemia, hepatitis hepatitis (including (including hepatitis hepatitis A, hepatitis A, hepatitis B, hepatitis B, and and hepatitis C), C),

hepatocellularcarcinoma, hepatocellular carcinoma, non-alcoholic non-alcoholic fatty fatty liver liver disease disease (NAFLD), (NAFLD), non-alcoholic non-alcoholic

steatohepatitis (NASH), steatohepatitis (NASH),liver livercancer, cancer, liverfibrosis, liver fibrosis,liver liverinflammation, inflammation, cholangiocarcinoma, cholangiocarcinoma,

angiosarcoma,hemangiosarcoma, angiosarcoma, hemangiosarcoma, and progressive and progressive familialfamilial intrahepatic intrahepatic cholestasis. cholestasis. In some In some embodiments, embodiments, thethe liver liver disease disease is is non-alcoholic non-alcoholic steatoheptatitis. steatoheptatitis. In some In some embodiments, embodiments, the the liver liver disease is disease is hepatocellular carcinoma. hepatocellular carcinoma.

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[0348] SomeSome

[0348] embodiments embodiments provided hereinherein provided provide provide for methods for methods of treating of treating non-alcoholic non-alcoholic 2023206094 18 Jul 2023

steatohepatitis (NASH) steatohepatitis (NASH) comprising comprising administering administering a therapeutically a therapeutically effective effective amount amount of a of a crystalline form crystalline formofofCompound Compound1 as 1described as described herein herein or a composition or a composition as described as described herein. herein.

[0349] SomeSome

[0349] embodiments embodiments hereinherein provided provided provide provide for the the use for use of aofcrystalline formofof a crystallineform Compound Compound 1 as 1described as described herein herein or a composition or a composition as described as described herein herein in in the treatment the treatment of of treating non-alcoholic treating steatohepatitis(NASH). non-alcoholic steatohepatitis (NASH).

[0350] SomeSome

[0350] embodiments embodiments provided hereinherein provided provide provide for methods for methods of treating of treating non-alcoholic non-alcoholic

steatohepatitis (NASH) steatohepatitis (NASH) comprising comprising administering administering a therapeutically a therapeutically effective effective amount amount of Form Iof Form I of Compound of Compound 1 1ororaa composition compositioncomprising comprisingForm FormI IofofCompound Compound1. 1.

[0351] SomeSome

[0351] embodiments embodiments provided hereinherein provided provide provide for the the use for use of Form I ofI Compound of Form of Compound 1 or 1 or a composition a compositioncomprising comprising FormForm I of Compound I of Compound 1 in the1treatment in the treatment of treating of treating non-alcoholic non-alcoholic

steatohepatitis (NASH). steatohepatitis (NASH).

[0352] SomeSome

[0352] embodiments embodiments provided hereinherein provided provide provide for methods for methods of treating of treating hepatocellular hepatocellular

carcinoma(HCC) carcinoma (HCC) comprising comprising administering administering a therapeutically a therapeutically effective effective amount amount of of a crystalline a crystalline

formofofCompound form Compound1 as 1described as described hereinherein or a composition or a composition as described as described herein. herein. Some Some embodiments embodiments provided provided herein herein provide provide foruse for the theofuse of a crystalline a crystalline form form of of Compound Compound 1 as 1 as describedherein described hereinorora acomposition composition as described as described herein herein in treatment in the the treatment of HCC. of HCC. In someIn some embodiments, embodiments, a crystalline a crystalline form form of Compound of Compound 1 is administered 1 is administered as an adjuvant as an adjuvant therapy. therapy. In some In some embodiments, embodiments, thethe crystalline crystalline form form of Compound of Compound 1 or composition 1 or composition describeddescribed herein areherein are administeredafter administered aftercurative curativesurgery, surgery,local localablation, ablation,ororliver livertransplantation. transplantation.

[0353] SomeSome

[0353] embodiments embodiments provided hereinherein provided provide provide for methods for methods of treating of treating hepatocellular hepatocellular

carcinoma(HCC) carcinoma (HCC) comprising comprising administering administering a therapeutically a therapeutically effective effective amount amount of Form I of of Form I of Compound Compound 1 ora acomposition 1 or compositioncomprising comprisingForm Form I ofCompound I of Compound1. 1.

[0354] In some

[0354] In some embodiments, embodiments, a method a method of treating of treating hepatocellularcarcinoma hepatocellular carcinoma (HCC) (HCC)

comprisesadministering comprises administering a therapeutically a therapeutically effective effective amount amount of a crystalline of a crystalline form form of of Compound Compound

1 as 1 as described hereinororaacomposition described herein compositionas as described described herein herein in combination in combination with surgical with surgical

resection, liver resection, liver transplantation, transplantation, radiofrequency ablation,percutaneous radiofrequency ablation, percutaneous ethanol ethanol injection, injection,

transarterial embolization, transarterial radiation, ororchemotherapy. embolization, radiation, chemotherapy. In some In some embodiments, embodiments, a methoda of method of treating hepatocellular treating carcinoma hepatocellular carcinoma (HCC) (HCC) comprises comprises administering administering a therapeutically a therapeutically effective effective

amount of amount of Form FormII of of Compound Compound 1 1orora acomposition compositioncomprising comprisingForm FormI IofofCompound Compound 1 1 in in combinationwith combination with surgical surgical resection, resection, liver liver transplation,radiofrequency transplation, radiofrequency ablation, ablation, percutaneous percutaneous

ethanol injection, ethanol injection, transarterial transarterial embolization, radiation,ororchemotherapy. embolization, radiation, chemotherapy. In some

[0355] In some

[0355] embodiments, embodiments, a provided a provided compound compound or composition, or composition, according according the method the method

of the of the present invention, may present invention, maybebe administered administered in combination in combination with sorafenib with sorafenib for thefor the treatment treatment of of hepatocellularcarcinoma. hepatocellular carcinoma.

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In some

[0356] In some

[0356] embodiments, embodiments, a provided a provided compound compound or composition, or composition, according according to to the the 2023206094 18 Jul 2023

methodofof method thepresent the presentinvention, invention, maymay be administered be administered using using any amount any amount and any and any route of route of administrationeffective administration effectivefor fortreating treatingororlessening lesseningthe theseverity severityofofa abacterial bacterialinfection infectionororinhibiting inhibiting the growth the growth ofofbacteria. bacteria.InInsome some embodiments, embodiments, the bacterial the bacterial infection infection is vulgaris. is acne acne vulgaris. In some

[0357] In some

[0357] embodiments, embodiments, a provided a provided compound compound or composition, or composition, according according to to the the methodofofthethepresent method presentinvention, invention, maymay be administered be administered using using any amount any amount and any and any route of route of administrationeffective administration effectivefor fortreating treatingororlessening lesseningthe theseverity severityofofa afungal fungalinfection infectionor or inhibiting inhibiting

the growth the growth ofoffungal fungalcells cells(Shen (Shen et et al.al."A"A Mechanism Mechanism forPotent for the the Potent Inhibition Inhibition of Eukaryotic of Eukaryotic

Acetyl-CoenzymeA ACarboxylase Acetyl-Coenzyme Carboxylase by by Soraphen Soraphen A, A, a Macrocyclic a Macrocyclic Polyketide Polyketide NaturalProduct" Natural Product" MolecularCell Molecular Cell(2004) (2004) 16, 16, 881-891). 881-891).

[0358] In some

[0358] In some embodiments, embodiments, a provided a provided compound compound inhibits inhibits onemore one or or more species species of fungi of fungi at at an MIC an MICof of 2 pg/mL 2 µg/mL or less. or less. In some In some embodiments, embodiments, a compound a compound of the of the present presentinhibits invention invention inhibits at least at least one one of of C. C. albicans, C. krusei, albicans, C. krusei, and andC.C.parapsilosis parapsilosisatata aconcentration concentrationof of 2 pg/mL 2 µg/mL or less. or less.

In some In embodiments, some embodiments, a compound a compound of the present of the present invention invention inhibits inhibits at leastatone least onealbicans, of C. of C. albicans, C. krusei, C. krusei, and and C.C. parapsilosis parapsilosis atata aconcentration concentrationof of 1 g/mL 1 µg/mL or less. or less. In some In some embodiments, embodiments, a a compound compound of the of the present present invention invention inhibits inhibits at least at least two two ofalbicans, of C. C. albicans, C. krusei, C. krusei, and and C. C. parapsilosis parapsilosis atataa concentration concentrationofof 2 2 pg/mL µg/mL or less. or less. In some In some embodiments, embodiments, a compound a compound of the of the present invention present inventioninhibits inhibitsatatleast least two twoofofC.C.albicans, albicans,C.C.krusei, krusei,andand C. C. parapsilosis parapsilosis at aat a concentrationofof1 1µg/mL concentration g/mL or less. or less. In some In some embodiments, embodiments, a compound a compound of theinvention of the present present invention inhibits each inhibits of C. each of C. albicans, albicans,C.C. krusei, krusei,and andC.C.parapsilosis parapsilosisat at a concentration a concentration of 2ofµg/mL 2 pg/mL or less. or less.

In some In embodiments, some embodiments, a compound a compound of the present of the present invention invention inhibits inhibits each of each of C. albicans, C. albicans, C. C. krusei, and krusei, and C. C. parapsilosis parapsilosis atata aconcentration concentrationof of 1 g/mL 1 µg/mL

[0359] In some

[0359] In some embodiments, embodiments, a provided a provided compound compound inhibits inhibits at least at least oneone of of Botrtyiscinerea, Botrtyis cinerea, Collectotrichumgraminicola, Collectotrichum graminicola, Diplodia Diplodia maydis, maydis, Fusarium Fusarium moniliforme, moniliforme, Fusarium virgulforme, Fusarium virguliforme,

Phytophthoracapsici, Phytophthora capsici, Rhizoctonia Rhizoctonia solani, solani, and and Septoria Septoria at a at a concentration concentration of 2 pg/mL of 2 µg/mL or less.or Inless. In someembodiments, some embodiments, a provided a provided compound compound inhibits inhibits at least at least one one of Botrtyis of Botrtyis cinerea, cinerea,

Collectotrichumgraminicola, Collectotrichum graminicola, Diplodia Diplodia maydis, maydis, Fusarium Fusarium moniliforme, moniliforme, Fusarium Fusarium virgulforme, virguliforme,

Phytophthoracapsici, Phytophthora capsici, Rhizoctonia Rhizoctonia solani, solani, and and Septoria Septoria at a at a concentration concentration of 1 org/mL of 1 µg/mL less.or Inless. In someembodiments, some embodiments, a compound a compound of the present of the present invention invention inhibits inhibits at least at least two two of Botrtyis of Botrtyis

cinerea,Collectotrichum cinerea, Collectotrichum graminicola, graminicola, Diplodia Diplodia maydis, maydis, Fusarium Fusarium moniliforme, moniliforme, Fusarium Fusarium

virguliforme,Phytophthora virguliforme, Phytophthora capsici, capsici, Rhizoctonia Rhizoctonia solani, solani, and Septoria and Septoria at a concentration at a concentration of 2 of 2 pg/mLor orless. µg/mL less.InInsome some embodiments, embodiments, a compound a compound of theinvention of the present present invention inhibits atinhibits at least least two two of Botrtyis of cinerea,Collectotrichum Botrtyis cinerea, Collectotrichum graminicola, graminicola, Diplodia Diplodia maydis, maydis, Fusarium Fusarium moniliforme, moniliforme,

Fusariumvirguliforme, Fusarium virguliforme, Phytophthora Phytophthora capsici, capsici, Rhizoctonia Rhizoctonia solani,solani, and Septoria and Septoria at a at a concentrationofof1 1µg/mL concentration g/mL or less. or less. In some In some embodiments, embodiments, a compound a compound of theinvention of the present present invention

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inhibits at inhibits at least leastthree three of ofBotrtyis Botrtyis cinerea, cinerea, Collectotrichum graminicola, Collectotrichum graminicola, Diplodia Diplodia maydis, maydis, 2023206094 18 Jul 2023

Fusarium Fusarium moniliforme, moniliforme, Fusarium Fusarium virguliforme, virguliforme, Phytophthora Phytophthora capsici,capsici, Rhizoctonia Rhizoctonia solani, solani, and and Septoria at Septoria at aa concentration concentrationofof2 2µg/mL pg/mL or less. or less. In some In some embodiments, embodiments, a compound a compound of the of the present invention present inventioninhibits inhibitsatat least least three three of of Botrtyis Botrtyis cinerea, cinerea,Collectotrichum Collectotrichum graminicola, graminicola,

Diplodiamaydis, Diplodia maydis, Fusarium Fusarium moniliforme, moniliforme, Fusarium Fusarium virguliforme, virguliforme, Phytophthora Phytophthora capsici, capsici, Rhizoctoniasolani, Rhizoctonia solani,andand Septoria Septoria at at a concentration a concentration of 1of 1 g/mL µg/mL or or less. less. In some

[0360] In some

[0360] embodiments, embodiments, a provided a provided compound compound or composition, or composition, according according to to the the methodofofthethepresent method presentinvention, invention, maymay be administered be administered using using any amount any amount and any and any route of route of administrationeffective administration effectivefor fortreating treatingororlessening lesseningthe theseverity severityofofa abacterial bacterialinfection infection(Tong, (Tong, L. L. et et al. J.J.Cell. al. Cell.Biochem. (2006)99, Biochem. (2006) 99,1476-1488). 1476-1488). In some

[0361] In some

[0361] embodiments, embodiments, a provided a provided compound compound or composition, or composition, according according to to the the methodofofthethepresent method presentinvention, invention, maymay be administered be administered using using any amount any amount and any and any route of route of administrationeffective administration effectivefor fortreating treatingororlessening lesseningthe theseverity severityofofa aviral viralinfection infection(Munger (Munger et al. et al.

Nat. Biotechnol.(2008) Nat. Biotechnol. (2008)26,26, 1179-1186). 1179-1186). In some In some embodiments, embodiments, the viralthe viral infection infection is Hepatitis is Hepatitis

C. InInsome C. someembodiments, embodiments, the viral the viral infection infection is Hepatitis is Hepatitis B. InB.some In embodiments, some embodiments, the viral the viral infection is infection is Hepatitis Hepatitis A. A.

In some

[0362] In some

[0362] embodiments, embodiments, a provided a provided compound compound or composition, or composition, according according to to the the methodofofthethepresent method presentinvention, invention, maymay be administered be administered using using any amount any amount and any and any route of route of administrationeffective administration effectivefor fortreating treatingororlessening lesseningthe theseverity severityofofa aneurological neurological disease disease

(Hendersonet etal.al.Neurotherapeutics (Henderson Neurotherapeutics (2008) (2008) 5, 470-480; 5, 470-480; Costantini Costantini et al. et al. Neurosci. Neurosci. (2008) (2008) 9 9 Suppl. 2:S16; Suppl. 2:S16;Baranano Baranano et al.Curr. et al. Curr. Treat.Opin. Treat. Opin. Neurol. Neurol. (2008) (2008) 10, 410-419). 10, 410-419).

In some

[0363] In some

[0363] embodiments, embodiments, a provided a provided compound compound or composition, or composition, according according to to the the methodofofthethepresent method presentinvention, invention, maymay be administered be administered using using any amount any amount and any and any route of route of administrationeffective administration effectivefor fortreating treatingororlessening lesseningthe theseverity severityofofa aparasitic parasiticinfection infectionororinhibiting inhibiting the growth the growth ofofparasites parasites(e.g. (e.g. malaria malariaand andtoxoplasma: toxoplasma: Gornicki Gornicki et"Apicoplast et al. al. "Apicoplast fatty fatty acid acid biosynthesisasasaatarget biosynthesis target for for medical medicalintervention interventionin inapicomplexan apicomplexan parasites" parasites" International International Journal Journal

of Parasitology of (2003)33,33,885-896; Parasitology (2003) 885-896; Zuther Zuther et al. et al. "Growth "Growth of Toxoplasma of Toxoplasma gondii gondii is is inhibited inhibited by by aryloxyphenoxypropionate herbicides aryloxyphenoxypropionate herbicides targeting targeting acetyl-CoA acetyl-CoA carboxylase" carboxylase" PNAS (1999) 9696(23) PNAS (1999) (23) 13387-13392). 13387-13392).

In some

[0364] In some

[0364] embodiments, embodiments, a provided a provided compound compound or composition, or composition, according according to to the the methodofofthethepresent method presentinvention, invention, maymay be administered be administered using using any amount any amount and any and any route of route of administrationeffective administration effectivefor fortreating treatingororlessening lesseningthe theseverity severityofofa acardiac cardiacdisorder. disorder.In In some some

embodiments, embodiments, thethe cardiac cardiac disorder disorder is cardiac is cardiac hypertrophy. hypertrophy. In embodiments In some some embodiments the cardiacthe cardiac disorder is disorder is treated treated or or its its severity severity lessened lessened by the cardioprotective by the cardioprotectivemechanism mechanism resulting resulting from from

increased fatty increased fatty acid acid oxidation oxidationvia viaACC ACC inhibition inhibition (Kolwicz (Kolwicz et al.et"Cardiac-specific al. "Cardiac-specific deletion deletion of of

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acetyl CoA acetyl carboxylase 22 (ACC2) CoA carboxylase prevents metabolic (ACC2) prevents metabolic remodeling remodelingduring during pressure-overload pressure-overload 2023206094 18 Jul 2023

hypertrophy" Circ. hypertrophy" Circ. Res. Res. (2012); (2012);DOI: DOI: 10.1161/CIRCRESAHA.112.268128). 10.1161/CIRCRESAHA.112.268128).

In certain

[0365] In certain

[0365] embodiments, embodiments, a provided a provided compound compound or composition, or composition, according according to the to the

methodofofthethepresent method presentinvention, invention, maymay be used be used as herbicides. as herbicides. In embodiments, In some some embodiments, the the present present invention provides invention providesa amethod method to inhibit to inhibit thethe growth growth or viability or viability of plants of plants comprising comprising treating treating

plants with plants with compounds compounds of the of the present present invention. invention. In embodiments In some some embodiments of theinvention, of the present present invention, a provided a compound provided compound or composition or composition can be can usedbetoused to inhibit inhibit the growth the growth or viability or viability ofby of plants plants by inhibiting ACC. inhibiting ACC.In In some some embodiments, embodiments, the method the method of the invention of the present present invention comprises comprises using a using a providedcompound provided compound or composition or composition to inhibit to inhibit fatty fatty acid production acid production in or increase in or increase fatty fatty acid acid oxidation inin plants. oxidation plants.

[0366] The The

[0366] exact exact amount amount required willwill required varyvary from from subjecttotosubject, subject depending on subject, depending the on the species, age, species, age, and andgeneral generalcondition conditionof of thesubject, the subject,thetheseverity severityof of theinfection, the infection,thetheparticular particular agent, its agent, its mode mode ofofadministration, administration,andand thethe like.A provided like. A provided compound compound or composition or composition of the of the invention isis preferably invention preferablyformulated formulatedin in dosage dosage unitunit formform for ease for ease of administration of administration and uniformity and uniformity

of dosage. of The dosage. The expression expression "dosage "dosage unit unit form"form" as herein as used used herein refers refers to a physically to a physically discrete discrete unit unit of agent of appropriatefor agent appropriate forthe thepatient patienttoto bebetreated. treated. ItItwill will be beunderstood, understood,however, however, thatthat the the total total

daily usage daily usageofofaa provided providedcompound compound or composition or composition of the of the present present invention invention will be will be by decided decided by the attending the attending physician physicianwithin within thethe scope scope of of sound sound medical medical judgment. judgment. The specific The specific effectiveeffective dose dose level for level for any particular patient any particular patient or or organism organismwill willdepend depend upon upon a variety a variety of factors of factors including including the the disorder being disorder beingtreated treatedand andthe theseverity severityofof thedisorder; the disorder;thetheactivity activityofofthe thespecific specificcompound compound employed;thethespecific employed; specificcomposition composition employed; employed; thebody the age, age,weight, body weight, general general health, health, sex sex and diet and diet of the of the patient; patient; the the time of administration, time of routeofofadministration, administration, route administration,andand rateof of rate excretion excretion of of thethe

specific compound specific compound employed; employed; the duration the duration of theof the treatment; treatment; drugsinused drugs used in combination combination or or coincidental with coincidental withthe thespecific specificcompound compound employed, employed, andfactors and like like factors wellinknown well known in the the medical medical arts. arts.

A pharmaceutically

[0367] A pharmaceutically

[0367] acceptable acceptable composition composition of this of this inventioncan invention to administered to canbebeadministered humansandand humans other other animals animals orally, orally, rectally, rectally, parenterally, parenterally, intracisternally, intracisternally, intravaginally, intravaginally,

intraperitoneally, topically intraperitoneally, topically (as (as by powders,ointments, by powders, ointments, or or drops), drops), bucally, bucally, as an as an oraloral or nasal or nasal

spray, or spray, or the the like, like, depending depending onon theseverity the severityofofthetheinfection infectionbeing being treated.In In treated. certain certain

embodiments, embodiments, a provided a provided compound compound of the invention of the invention may be administered may be administered orally or parenterally orally or parenterally

at dosage at levels ofofabout dosage levels about0.01 0.01mg/kg mg/kg to about to about 50 mg/kg 50 mg/kg and preferably and preferably from1 about from about 1 mg/kg mg/kg to to about 2525mg/kg, about mg/kg,of of subject subject body body weight weight per day, per day, one one or or times more more atimes day, a today, to obtain obtain the desired the desired

therapeutic effect. therapeutic effect.

[0368] LiquidLiquid

[0368] dosagedosage forms forms for oralfor oral administration administration include, include, butlimited but are not are notto, limited to, pharmaceuticallyacceptable pharmaceutically acceptable emulsions, emulsions, microemulsions, microemulsions, solutions, solutions, suspensions, suspensions, syrups syrups and and

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elixirs. In elixirs. In addition to the addition to the active compounds, active compounds, thethe liquid liquid dosage dosage forms forms may contain may contain inert diluents inert diluents 2023206094 18 Jul 2023

commonly commonly usedused in the in the art art suchsuch as, as, for for example, example, waterwater or other or other solvents, solvents, solubilizing solubilizing agentsagents and and emulsifiers such emulsifiers suchasasethyl ethylalcohol, alcohol,isopropyl isopropyl alcohol, alcohol, ethyl ethyl carbonate, carbonate, ethyl ethyl acetate, acetate, benzyl benzyl

alcohol, benzyl alcohol, benzylbenzoate, benzoate,propylene propylene glycol, glycol, 1,3-butylene 1,3-butylene glycol, glycol, dimethylformamide, dimethylformamide, oils (in oils (in particular, cottonseed, particular, groundnut,corn, cottonseed, groundnut, corn,germ, germ, olive, olive, castor, castor, andand sesame sesame oils), oils), glycerol, glycerol,

tetrahydrofurfurylalcohol, tetrahydrofurfuryl alcohol,polyethylene polyethylene glycols glycols and and fatty fatty acidacid esters esters of sorbitan, of sorbitan, and and mixtures mixtures

thereof. Besides thereof. Besidesinert inertdiluents, diluents,the theoral oralcompositions compositionscancan alsoalso include include adjuvants adjuvants such such as as wetting wetting

agents, emulsifying agents, emulsifyingandand suspending suspending agents, agents, sweetening, sweetening, flavoring, flavoring, and perfuming and perfuming agents. agents. Injectable

[0369] Injectable

[0369] preparations, preparations, for example, sterile sterile for example, injectable aqueousaqueous injectable or oleaginous or oleaginous

suspensionsmay suspensions maybe be formulated formulated according according to thetoknown the known artsuitable art using using suitable dispersing dispersing or or wetting wetting agents and agents andsuspending suspending agents. agents. The The sterile sterile injectable injectable preparation preparation maybealso may also be a sterile a sterile injectable injectable

solution, suspension solution, suspensionororemulsion emulsion innontoxic in a a nontoxic parenterally parenterally acceptable acceptable diluent diluent or solvent, or solvent, for for example,asasa asolution example, solutioninin1,3-butanediol. 1,3-butanediol.Among Among the acceptable the acceptable vehicles vehicles and solvents and solvents that may that may be employed be employed areare water, water, Ringer's Ringer's solution, solution, U.S.P. U.S.P. and isotonic and isotonic sodium sodium chloride chloride solution. solution. In In addition, sterile, addition, sterile, fixed fixed oils oilsare areconventionally employed conventionally employed as as a solvent a solvent or or suspending suspending medium. medium. For For this purpose this anybland purpose any blandfixed fixed oiloil can can bebe employed employed including including synthetic synthetic mono- mono- or diglycerides. or diglycerides. In In addition, fatty addition, fatty acids such asas oleic acids such oleic acid acid are are used usedininthe thepreparation preparationofofinjectables. injectables.

[0370] The injectable

[0370] The injectable formulations formulations can be sterilized, can be sterilized, for example, for example, by filtration by filtration through through a a bacterial-retaining filter, bacterial-retaining filter, ororby by incorporating sterilizing agents incorporating sterilizing in the agents in the form formofofsterile sterile solid solid compositionswhich compositions which can can be dissolved be dissolved or dispersed or dispersed in sterile in sterile waterwater or other or other sterile sterile injectable injectable

medium medium prior prior to to use. use.

In order

[0371] In order

[0371] to prolong to prolong the effect the effect of a provided of a provided compound, compound, it is it is often often desirable desirable to slow to slow the absorption the absorptionofofaacompound compoundfromfrom subcutaneous subcutaneous or intramuscular or intramuscular injection. injection. This may This be may be accomplished accomplished by by thethe useuse of aofliquid a liquid suspension suspension of crystalline of crystalline or amorphous or amorphous material material with with poor poor watersolubility. water solubility. The Therate rateofofabsorption absorptionof of thethe compound compound then depends then depends upon upon its rate its of rate of dissolution that, dissolution that, in in turn, turn, may dependupon may depend upon crystal crystal size size andand crystalline crystalline form. form. Alternatively, Alternatively,

delayedabsorption delayed absorptionofof a parenterally a parenterally administered administered compound compound form is form is accomplished accomplished by dissolving by dissolving

or suspending or suspending a a compound compound in aninoil an vehicle. oil vehicle. Injectable Injectable depot depot forms forms arebymade are made by forming forming microencapsule microencapsule matrices matrices of aof a compound compound in biodegradable in biodegradable polymerspolymers such as polylactide such as polylactide-

polyglycolide.Depending polyglycolide. Depending upon upon the ratio the ratio of compound of compound to polymer to polymer and the and the nature of nature the of the particular polymer particular polymeremployed, employed, the the raterate of compound of compound releaserelease can be can be controlled. controlled. ExamplesExamples of of other biodegradable other biodegradablepolymers polymers include include poly(orthoesters) poly(orthoesters) and poly(anhydrides). and poly(anhydrides). Depot injectable Depot injectable

formulationsare formulations arealso alsoprepared preparedby by entrapping entrapping a compound a compound in liposomes in liposomes or microemulsions or microemulsions that that are compatible are compatiblewith withbody body tissues. tissues.

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Compositions

[0372] Compositions

[0372] for or for rectal rectal or vaginal vaginal administration administration are preferably are preferably suppositories suppositories which which 2023206094 18 Jul 2023

can be can be prepared preparedbybymixing mixing the the compounds compounds of thisof this invention invention with suitable with suitable non-irritating non-irritating

excipients ororcarriers excipients carriers such suchasascocoa cocoabutter, butter,polyethylene polyethylene glycol glycol or aorsuppository a suppository wax which wax which are are solid at solid at ambient temperature ambient temperature butbut liquid liquid at at body body temperature temperature and therefore and therefore melt melt in the in the rectum rectum or or vaginal cavity vaginal cavityand andrelease releasethe theactive activecompound. compound.

[0373] Solid Solid

[0373] dosagedosage forms forms for oralfor oral administration administration include capsules, include capsules, tablets,powders, tablets, pills, pills, powders, and granules. and granules. InInsuch such soliddosage solid dosage forms, forms, the the active active compound compound is with is mixed mixed at with least at least one one inert, inert, pharmaceuticallyacceptable pharmaceutically acceptable excipient excipient or carrier or carrier suchsuch as sodium as sodium citrate citrate or dicalcium or dicalcium phosphate phosphate

and/or a)a) fillers and/or fillers or or extenders suchasas starches, extenders such starches, lactose, lactose, sucrose, sucrose, glucose, glucose,mannitol, mannitol,andand silicic silicic

acid, b) acid, b) binders suchas, binders such as, for for example, example,carboxymethylcellulose, carboxymethylcellulose, alginates, alginates, gelatin, gelatin,

polyvinylpyrrolidinone,sucrose, polyvinylpyrrolidinone, sucrose, andand acacia, acacia, c) humectants c) humectants such such as as glycerol, glycerol, d) disintegrating d) disintegrating

agents such agents suchasasagar-agar, agar-agar,calcium calcium carbonate, carbonate, potato potato or tapioca or tapioca starch, starch, alginic alginic acid,acid, certain certain

silicates, and silicates, and sodium carbonate,e) e)solution sodium carbonate, solutionretarding retarding agents agents such such as paraffin, as paraffin, f) absorption f) absorption

accelerators such accelerators suchasasquaternary quaternaryammonium ammonium compounds, compounds, g) agents g) wetting wetting agents such such as, for as, for example, example, cetyl alcohol cetyl alcohol and andglycerol glycerolmonostearate, monostearate, h) absorbents h) absorbents such such as kaolin as kaolin and bentonite and bentonite clay, clay, and i) and i) lubricants such lubricants suchasastalc, talc, calcium calciumstearate, stearate, magnesium magnesium stearate, stearate, solid solid polyethylene polyethylene glycols, glycols, sodium sodium

lauryl sulfate, lauryl sulfate, and mixturesthereof. and mixtures thereof. InInthethecase caseofof capsules,tablets capsules, tabletsandand pills,the pills, thedosage dosage form form

mayalso may alsocomprise comprise buffering buffering agents. agents.

[0374] Solid Solid

[0374] compositions compositions of a similar of a similar alsomay type maytype be employed employed also be as fillers in fillersandinhard- as soft soft and hard filled gelatin filled gelatin capsules using such capsules using suchexcipients excipientsasaslactose lactoseorormilk milk sugar sugar as as well well as as high high molecular molecular

weightpolyethylene weight polyethylene glycols glycols and and the the like. like. The The solidsolid dosage dosage forms forms of tablets, of tablets, dragees, dragees, capsules, capsules,

pills, and pills, and granules can bebeprepared granules can preparedwith with coatings coatings and and shells shells suchsuch as enteric as enteric coatings coatings and other and other

coatings well coatings wellknown knownin in thethe pharmaceutical pharmaceutical formulating formulating art. may art. They They may optionally optionally contain contain opacifyingagents opacifying agentsandand cancan also also be be of of a composition a composition that that they they release release the active the active ingredient(s) ingredient(s)

only, or only, or preferentially, preferentially, in in aa certain certain part part of of the the intestinal intestinaltract, optionally, tract, optionally,inin a delayed a delayedmanner. manner.

Examples Examples of of embedding embedding compositions compositions that that can be can usedbe used include include polymericpolymeric substancessubstances and waxes. and waxes. Solid compositions Solid compositionsof of a similar a similar type type maymay alsoalso be employed be employed as fillers as fillers in soft in soft and hard-filled and hard-filled

gelatin capsules gelatin capsules using usingsuch suchexcipients excipientsas as lactose lactose or or milk milk sugar sugar as well as well as high as high molecular molecular weightweight

polethyleneglycols polethylene glycolsandand thethe like. like.

[0375] A provided

[0375] A provided compound compound can also alsoinbemicro-encapsulated can be formform in micro-encapsulated one one withwith or more or more

excipients asas noted excipients notedabove. above.TheThe solid solid dosage dosage formsforms of tablets, of tablets, dragees, dragees, capsules, capsules, pills,pills, and and granules can granules canbebeprepared prepared with with coatings coatings and and shells shells suchsuch as enteric as enteric coatings, coatings, release release controlling controlling

coatings and coatings andother othercoatings coatingswell well known known in pharmaceutical in the the pharmaceutical formulating formulating art. In art. such In such solid solid dosageforms dosage formsthetheactive activecompound compound may bemay be admixed admixed with one with at least at least inertone inert such diluent diluent as such as sucrose, lactose sucrose, lactose oror starch. starch. Such Suchdosage dosage forms forms may comprise, may also also comprise, as is normal as is normal practice, practice,

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additional substances additional substancesother otherthan than inertdiluents, inert diluents,e.g., e.g., tableting tabletinglubricants lubricantsand andother othertableting tabletingaids aids 2023206094 18 Jul 2023

such aa magnesium such magnesium stearate stearate and and microcrystalline microcrystalline cellulose. cellulose. In theIncase the of case of capsules, capsules, tablets tablets and and pills, the pills, thedosage formsmay dosage forms may also also comprise comprise buffering buffering agents. agents. They They may may optionally optionally contain contain opacifyingagents opacifying agentsand and cancan also also be be ofcomposition of a a composition that that they they release release the active the active ingredient(s) ingredient(s)

only, or only, or preferentially, preferentially, in in aa certain certain part part of of the the intestinal intestinaltract, optionally, tract, optionally,inin a delayed a delayedmanner. manner.

Examples Examples of of embedding embedding compositions compositions that that can be can usedbe used include include polymericpolymeric substancessubstances and waxes. and waxes.

[0376] Dosage

[0376] Dosage forms forms for topical or or for topical transdermaladministration transdermal this compoundofofthis administrationofofaa compound invention include invention includeointments, ointments, pastes,creams, pastes, creams, lotions, lotions, gels, gels, powders, powders, solutions, solutions, sprays, sprays, inhalants inhalants

or patches. or Theactive patches. The activecomponent component is admixed is admixed under under sterilesterile conditions conditions with a with a pharmaceutically pharmaceutically

acceptablecarrier acceptable carrier and andany anyneeded needed preservatives preservatives or buffers or buffers as be as may may be required. required. Ophthalmic Ophthalmic

formulation,ear formulation, eardrops, drops,and andeyeeye drops drops areare also also contemplated contemplated as being as being withinwithin the of the scope scope thisof this

invention. Additionally, invention. Additionally,thethepresent present invention invention contemplates contemplates theofuse the use of transdermal transdermal patches, patches,

whichhave which havethetheadded added advantage advantage of providing of providing controlled controlled delivery delivery of a compound of a compound to the to the body. body. Suchdosage Such dosageforms forms cancan be made be made by dissolving by dissolving or dispensing or dispensing the compound the compound in the in the proper proper medium.Absorption medium. Absorption enhancers enhancers canbealso can also usedbe toused to increase increase the fluxthe of flux of the compound the compound across the across the skin. The skin. Therate ratecan canbebecontrolled controlledby by either either providing providing a rate a rate controlling controlling membrane membrane or by or by dispersing the dispersing thecompound compoundin ainpolymer a polymer matrix matrix or or gel. gel.

[0377] According

[0377] According to one to one embodiment, embodiment, the invention the invention relates relates totoa amethod methodofofinhibiting inhibiting ACC ACC

in aa biological in samplecomprising biological sample comprisingthethe step step of contacting of contacting saidsaid biological biological sample sample with awith a provided provided

compound,ororaa composition compound, composition comprising comprising said said compound. compound.

[0378] In certain

[0378] In certain embodiments, embodiments, the invention the invention relates relates to to aofmethod a method of modulating modulating fatty acid fatty acid levels in levels in aa biological samplecomprising biological sample comprisingthethe step step of of contacting contacting saidsaid biological biological sample sample with awith a provided compound, provided compound,ororaa composition composition comprising comprising said said compound. compound.

[0379] The term

[0379] The"biological term "biological sample",sample", as usedincludes, as used herein, herein, includes, without limitation, without limitation, cell cell cultures or cultures or extracts extracts thereof; thereof; biopsied biopsiedmaterial materialobtained obtained from from a mammal a mammal or extracts or extracts thereof; thereof; and and blood, saliva, blood, saliva, urine, urine, feces, feces, semen, tears, or semen, tears, or other other body bodyfluids fluidsororextracts extractsthereof. thereof.

[0380] Inhibition

[0380] Inhibition of enzymes of enzymes in a biological in a biological sample is usefulisfor sample useful for a variety a variety of purposes of purposes that that are known are known toto one one of of skillininthe skill theart. art. Examples Examples of such of such purposes purposes include, include, butnot but are arelimited not limited to to biological assays, biological assays, gene geneexpression expression studies, studies, andand biological biological target target identification. identification.

[0381] Another

[0381] Another embodiment embodiment of theofpresent the present invention invention relatestotoa amethod relates methodofofinhibiting inhibiting ACC ACC

in aa patient in patient comprising thestep comprising the stepofofadministering administeringto to said said patient patient a provided a provided compound, compound, or a or a composition comprising composition comprising said said compound. compound.

[0382] According

[0382] According to another to another embodiment, embodiment, the the invention invention relatestotoaamethod relates methodofofinhibiting inhibiting fatty acid fatty acid production, stimulatingfatty production, stimulating fattyacid acidoxidation, oxidation,ororboth, both,inina apatient patientcomprising comprisingthe the stepstep

of administering of administering totosaid saidpatient patienta aprovided provided compound, compound, or a or a composition composition comprising comprising said said

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compound. compound. According According to certain to certain embodiments, embodiments, the invention the invention relates relates to to aofmethod a method of inhibiting inhibiting 2023206094 18 Jul 2023

fatty acid fatty acid production, stimulatingfatty production, stimulating fattyacid acidoxidation, oxidation,ororboth both in in a a patient,leading patient, leadingto todecreasing decreasing obesity or obesity or alleviating alleviating symptoms symptoms of metabolic of metabolic syndrome, syndrome, comprising comprising the stepthe of step of administering administering to to said patient said patient aa provided compound, provided compound, or aor a composition composition comprising comprising said compound. said compound. In other In other embodiments, embodiments, thethe present present invention invention provides provides a method a method for treating for treating a disorder a disorder mediated mediated by ACC, by ACC, in aa patient in patient in in need need thereof, comprisingthethestep thereof, comprising stepofofadministering administering to said to said patient patient a provided a provided

compound compound or pharmaceutically or pharmaceutically acceptable acceptable composition composition thereof. thereof Such disorders Such disorders are in are described described in detail herein. detail herein.

In some

[0383] In some

[0383] embodiments, embodiments, a provided a provided compound compound or composition or composition thereof thereof may may be be used used in in a method a methodofoftreating treatingobesity obesityororanother another metabolic metabolic disorder. disorder. In certain In certain embodiments, embodiments, a provided a provided

compound compound or composition or composition thereof thereof may bemay usedbe toused treattoobesity treat obesity ormetabolic or other other metabolic disorder disorder in a in a mammal.In Incertain, mammal. certain, embodiments embodimentsthe themammal mammalis is a human a human patient.InIncertain patient. certain embodiments, embodiments,aa providedcompound provided compound or composition or composition thereofthereof may be may used be to used treat to treat obesity obesity or other or other metabolic metabolic

disorder in disorder in aa human humanpatient. patient.

[0384] In some

[0384] In some embodiments, embodiments, the present the present invention invention provides provides a method a method of of treatingobesity treating obesity or or another metabolic another metabolicdisorder, disorder,comprising comprising administering administering a provided a provided compound compound or composition or composition

thereof to thereof to aa patient patient with obesityororanother with obesity anothermetabolic metabolic disorder. disorder. In certain In certain embodiments, embodiments, the the methodofoftreating method treatingobesity obesityor oranother another metabolic metabolic disorder disorder comprises comprises administering administering a provided a provided

compoundororcomposition compound compositionthereof thereofto to aa mammal. mammal. InIncertain certain embodiments, embodiments, the the mammal mammal is isa a

human.In In human. some some embodiments, embodiments, the metabolic the metabolic disorderdisorder is dyslipidemia is dyslipidemia or hyperlipidemia. or hyperlipidemia. In In someembodiments, some embodiments, the obesity the obesity is a is a symptom symptom of Prader-Willi of Prader-Willi syndrome, syndrome, Bardet-Biedl Bardet-Biedl

syndrome, Cohen syndrome, Cohensyndrome syndromeor or MOMO MOMO syndrome. syndrome. In embodiments, In some some embodiments, the obesity the obesity is a is a side side effect of effect of the the administration ofanother administration of anothermedication, medication, including including but but not not limited limited to insulin, to insulin,

sulfonylureas, thiazolidinediones, sulfonylureas, thiazolidinediones,antipsychotics, antipsychotics, antidepressants, antidepressants, steroids, steroids, anticonvulsants anticonvulsants

(including phenytoin (including phenytoinandand valproate), valproate), pizotifen, pizotifen, or hormonal or hormonal contraceptives. contraceptives.

[0385] In certain

[0385] In certain embodiments, embodiments, the present the present invention provides provides invention a method of treating of a method treating cancer or cancer or another proliferative another proliferative disorder, disorder, comprising comprising administering administering a provided a provided compound compound or composition or composition

thereof to thereof to aa patient patient with cancerororanother with cancer anotherproliferative proliferativedisorder. disorder.In In certain certain embodiments, embodiments, the the methodofoftreating method treatingcancer cancer or or another another proliferative proliferative disorder disorder comprises comprises administering administering a provided a provided

compoundororcomposition compound compositionthereof thereofto to aa mammal. mammal. InIncertain certain embodiments, embodiments, the the mammal mammal is isa a

human. human.

[0386] As used

[0386] used herein, As herein, the terms terms "inhibition the "inhibition of cancer" of cancer" and "inhibition of cancerof and "inhibition cancer cell cell proliferation" refer proliferation" refer to to the the inhibition, inhibition, or or decrease in the decrease in the rate, rate, of of the the growth, division, maturation growth, division, maturation or viability or viability of of cancer cells, and/or cancer cells, causing the and/or causing thedeath deathofofcancer cancercells, cells,individually individuallyororininaggregate aggregate with other with othercancer cancercells, cells, by bycytotoxicity, cytotoxicity,nutrient nutrientdepletion, depletion,ororthe theinduction induction of of apoptosis. apoptosis.

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[0387] Examples

[0387] Examples of tissues of tissues containing containing cancerous cancerous cells cells whose whose proliferation proliferation is by is inhibited inhibited the by the 2023206094 18 Jul 2023

a provided a compound provided compound or composition or composition thereof thereof described described herein herein and and which against against thewhich the methods methods describedherein described hereinare areuseful usefulinclude includebutbut areare notnot limited limited to to breast,prostate, breast, prostate,brain, brain,blood, blood,bone bone marrow,liver, marrow, liver,pancreas, pancreas,skin, skin,kidney, kidney,colon, colon, ovary, ovary, lung, lung, testicle,penis, testicle, penis,thyroid, thyroid,parathyroid, parathyroid, pituitary, thymus, pituitary, retina, uvea, thymus, retina, uvea, conjunctiva, conjunctiva,spleen, spleen,head, head,neck, neck, trachea, trachea, gall gall bladder, bladder, rectum, rectum,

salivary gland, salivary gland, adrenal adrenalgland, gland,throat, throat,esophagus, esophagus, lymph lymph nodes, nodes, sweatsweat glands, glands, sebaceous sebaceous glands, glands,

muscle,heart, muscle, heart, and andstomach. stomach. In some

[0388] In some

[0388] embodiments, embodiments, the cancer the cancer treated by by treated a provided a provided compound compound or composition or composition

thereof is thereof is aa melanoma, liposarcoma, melanoma, liposarcoma, lunglung cancer, cancer, breast breast cancer, cancer, prostate prostate cancer, cancer, leukemia, leukemia,

kidneycancer, kidney cancer,esophageal esophageal cancer, cancer, brain brain cancer, cancer, lymphoma lymphoma or colonorcancer. colon cancer. In In certain certain embodiments, embodiments, thethe cancer cancer is aisprimary a primary effusion effusion lymphoma lymphoma (PEL). (PEL). In certainInpreferred certain preferred embodiments, embodiments, thethe cancer cancer to treated to be be treated by aby a provided provided compound compound or composition or composition thereof isthereof one is one bearing an bearing an activated activatedMAPK pathway.InInsome MAPK pathway. someembodiments, embodiments, thethe cancerbearing cancer bearingananactivated activated MAPK MAPK pathway pathway is melanoma. is a a melanoma. In certainpreferred In certain preferredembodiments, embodiments,thethecancer cancertreated treated by a by a

provided compound provided compoundororcomposition compositionthereof thereofis is one one associated associatedwith withBRCA1 mutation. InIn an BRCA1 mutation. an especially preferred especially preferredembodiment, embodiment,the the cancer cancer treated treated by a by a provided provided compound compound or composition or composition

thereof is thereof is aa triple triplenegative negative breast breast cancer. cancer.

[0389] In certain

[0389] In certain embodiments, embodiments, thethe diseaseswhich diseases which canbebetreated can treated by by aa provided provided compound compound or composition or thereof composition thereof areneurological are neurological disorders. disorders. In some In some embodiments, embodiments, the neurological the neurological

disorder is disorder is Alzheimer's Alzheimer'sDisease, Disease, Parkinson's Parkinson's Disease, Disease, epilepsy, epilepsy, ischemia, ischemia, Age Associated Age Associated

MemoryImpairment, Memory Impairment,Mild Mild CognitiveImpairment, Cognitive Impairment,Friedreich's Friedreich'sAtaxia, Ataxia, GLUT1-deficient GLUTI-deficient epilepsy, Leprechaunism, epilepsy, Leprechaunism, Rabson-Mendenhall Syndrome, Rabson-Mendenhall Syndrome, Coronary Coronary ArterialBypass Arterial Bypass Graft Graft

dementia,anaesthesia-induced dementia, anaesthesia-induced memory memory loss, amyotrophic loss, amyotrophic lateral lateral sclerosis, sclerosis, glioma glioma or or Huntington'sDisease. Huntington's Disease.

[0390] In certain

[0390] In certain embodiments, thethe embodiments, disease which diseasewhich canbebetreated can by aa provided treated by compoundoror provided compound compositionthereof composition thereof is is anan infectiousdisease. infectious disease.In In some some embodiments, embodiments, the infectious the infectious disease disease is a is a viral infection. viral In some infection. In someembodiments embodiments the viral the viral infection infection is cytomegalovirus is cytomegalovirus infection infection or or influenza infection. influenza infection. InInsome some embodiments, embodiments, the infectious the infectious disease disease is a fungal is a fungal infection. infection. In someIn some embodiments, embodiments, thethe infectious infectious disease disease is aisbacterial a bacterial infection. infection.

[0391] Depending

[0391] upon theupon Depending the particular particular condition, condition, or disease, or disease, to be treated, to be treated, additional additional

therapeutic agents, therapeutic agents, which whicharearenormally normally administered administered to treat to treat that that condition, condition, may may be be administered administered

in combination in with combination with a provided a provided compound compound or composition or composition thereof. thereof. As usedadditional As used herein, herein, additional therapeutic agents therapeutic agentsthat thatare are normally normallyadministered administered to treat to treat a particular a particular disease, disease, or or condition, condition, are are

knownas as"appropriate known "appropriate for for thethe disease, disease, or condition, or condition, being being treated." treated."

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In certain

[0392] In certain

[0392] embodiments, embodiments, a provided a provided compound compound or composition or composition thereof thereof is is 2023206094 18 Jul 2023

administeredinincombination administered combinationwithwith one one or more or more additional additional antifungal antifungal (antimycotic) (antimycotic) agents agents for the for the treatmentofofaa fungal treatment fungalinfection. infection.InInsome some embodiments, embodiments, theorone the one moreoradditional more additional antifungal antifungal

(antimycotic)agents (antimycotic) agentsareareselected selectedfrom from polyene polyene antifungals antifungals (including (including butlimited but not not limited to to amphotericinB B amphotericin (as(as amphotericin amphotericin B deoxycholate, B deoxycholate, amphotericin amphotericin B lipid complex, B lipid complex, or or liposomal liposomal amphotericinB),B),candicidin, amphotericin candicidin, filipin,hamycin, filipin, hamycin, natamycin, natamycin, nystatin, nystatin, and rimocidin), and rimocidin), azole azole antifungals (including antifungals (includingbut butnot notlimited limitedtotoabafungin, abafungin, albaconazole, albaconazole, bifonazole, bifonazole, butoconazole, butoconazole,

clotrimazole, econazole, clotrimazole, econazole,efinaconazole, efinaconazole, epoxiconazole, epoxiconazole, fenticonazole, fenticonazole, fluconazole, fluconazole,

isavuconazole,isoconazole, isavuconazole, isoconazole, itraconazole, itraconazole, ketoconazole, ketoconazole, luliconazole, luliconazole, miconazole, miconazole, omoconazole, omoconazole,

oxiconazole,posaconazole, oxiconazole, posaconazole, propiconazole, propiconazole, ravuconazole, ravuconazole, sertaconazole, sertaconazole, sulconazole, sulconazole,

terconazole, tioconazole, terconazole, tioconazole,and andvoriconazole), voriconazole), allylamines allylamines (including (including butlimited but not not limited to amorolfin, to amorolfin,

butenafine, naftifine, butenafine, naftifine, and andterbinafine), terbinafine), echinocandins echinocandins (including (including but but not not limited limited to anidulafungin, to anidulafungin,

caspofungin,and caspofungin, andmicafungin), micafungin), benzoic benzoic acid,acid, ciclopirox, ciclopirox, flucytosine, flucytosine, griseofulvin, griseofulvin, haloprogin, haloprogin,

tolnaftate, undecylenic tolnaftate, acid,and undecylenic acid, andcrystal crystalviolet. violet. In certain

[0393] In certain

[0393] embodiments, embodiments, a provided a provided compound compound or composition or composition thereof thereof is is administeredinincombination administered combinationwithwith another another inhibitor inhibitor ofor of ACC ACC or antiobesity antiobesity agent. agent. In some In some embodiments, embodiments, a provided a provided compound compound or composition or composition thereof thereof is is administered administered in combination in combination with with one or one or more moreother othertherapeutic therapeutic agents. agents. SuchSuch therapeutic therapeutic agents agents include, include, butnotarelimited but are not limited to to agents such agents suchasasorlistat orlistat (Xenical), (Xenical), CNS CNS stimulants, stimulants, Qsymia, Qsymia, or Belviq. or Belviq.

[0394] In certain

[0394] In certain embodiments, embodiments, a provided a provided compound or aor compound a composition composition thereof thereof is is administeredinincombination administered combinationwithwith another another anti-cancer, anti-cancer, cytotoxin, cytotoxin, or chemotherapeutic or chemotherapeutic agent, toagent, a to a patient in patient in need thereof. need thereof.

[0395] In certain

[0395] In certain embodiments, embodiments, thethe anti-cancerororchemotherapeutic anti-cancer chemotherapeuticagents agentsused usedin in combinationwith combination with a provided a provided compound compound or composition or composition thereof include, thereof include, butlimited but are not are notto, limited to, metformin,phenformin, metformin, phenformin, buformin, buformin, imatinib, imatinib, nilotinib, nilotinib, gefitinib, gefitinib, sunitinib, sunitinib, carfilzomib, carfilzomib,

salinosporamideA, A, salinosporamide retinoic retinoic acid, acid, cisplatin,carboplatin, cisplatin, carboplatin,oxaliplatin, oxaliplatin,mechlorethamine, mechlorethamine, cyclophosphamide, cyclophosphamide, chlorambucil, chlorambucil, ifosfamide, ifosfamide, azathioprine, azathioprine, mercaptopurine, mercaptopurine, doxifluridine, doxifluridine,

fluorouracil, gemcitabine, fluorouracil, gemcitabine,methotrexate, methotrexate, tioguanine, tioguanine, vincristine, vincristine, vinblastine, vinblastine, vinorelbine, vinorelbine,

vindesine, podophyllotoxin, vindesine, podophyllotoxin, etoposide, etoposide, teniposide, teniposide, tafluposide, tafluposide, paclitaxel, paclitaxel, docetaxel, docetaxel, irinotecan, irinotecan,

topotecan, amsacrine, topotecan, amsacrine,actinomycin, actinomycin, doxorubicin, doxorubicin, daunorubicin, daunorubicin, valrubicin, valrubicin, idarubicin, idarubicin,

epirubicin, plicamycin, epirubicin, plicamycin,mitomycin, mitomycin, mitoxantrone, mitoxantrone, melphalan, melphalan, busulfan, busulfan, capecitabine, capecitabine,

pemetrexed,epothilones, pemetrexed, epothilones, 13-cis-Retinoic 13-cis-Retinoic Acid, Acid, 2-CdA, 2-CdA, 2-Chlorodeoxyadenosine, 2-Chlorodeoxyadenosine, 5-Azacitidine, 5-Azacitidine,

5-Fluorouracil, 5-FU, 5-Fluorouracil, 5-FU,6-Mercaptopurine, 6-Mercaptopurine, 6-MP, 6-MP, 6-TG, 6-TG, 6-Thioguanine, 6-Thioguanine, Abraxane, Accutane R, Abraxane, Accutane @, Actinomycin-D,Adriamycin Actinomycin-D, Adriamycin®,@,Adrucil Adrucil®,@,Afinitor Afinitor®, @, Agrylin Agrylin ®, @, Ala-Cort Ala-Cort ®, @, Aldesleukin, Aldesleukin, Alemtuzumab,ALIMTA, Alemtuzumab, ALIMTA, Alitretinoin, Alitretinoin, Alkaban-AQ Alkaban-AQ @, Alkeran R, Alkeran @, All-transretinoicAcid, ®, All-transretinoic Acid,

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AlphaInterferon, Alpha Interferon,Altretamine, Altretamine, Amethopterin, Amethopterin, Amifostine, Amifostine, Aminoglutethimide, Aminoglutethimide, Anagrelide, Anagrelide, 2023206094 18 Jul 2023

AnandronR,@,Anastrozole, Anandron Anastrozole, Arabinosylcytosine, Arabinosylcytosine, Ara-C, Aranesp @, Aredia Aranesp ®, Aredia ®, @, Arimidex Arimidex®,@, AromasinR,@, Arranon Aromasin Arranon®,@,Arsenic ArsenicTrioxide, Arzerra T MAsparaginase, Trioxide, Arzerra, , Asparaginase,ATRA, ATRA, Avastin Avastin R, @, Azacitidine, BCG, Azacitidine, BCNU,Bendamustine, BCG, BCNU, Bendamustine, Bevacizumab, Bevacizumab, Bexarotene, Bexarotene, BEXXAR BEXXAR R, @, Bicalutamide, BiCNU, Bicalutamide, Blenoxane®,@,Bleomycin, BiCNU, Blenoxane Bleomycin, Bortezomib, Bortezomib, Busulfan, Busulfan, Busulfex Busulfex R, @, C225, C225,

Calcium Leucovorin, Calcium Leucovorin, Campath Campath®,@,Camptosar Camptosar ®, @, Camptothecin-11, Camptothecin-11, Capecitabine, Capecitabine, CaracTM,TM, Carac

Carboplatin, Carmustine, Carboplatin, Carmustine, Carmustine Carmustine Wafer, Wafer, Casodex @, CC-5013, Casodex R, CC-5013,CCI-779, CCI-779,CCNU, CCNU, CDDP, CDDP,

CeeNU,Cerubidine CeeNU, Cerubidine®,@,Cetuximab, Cetuximab,Chlorambucil, Chlorambucil,Citrovorum Citrovorum Factor,Cladribine, Factor, Cladribine, Cortisone, Cortisone, CosmegenR,@,CPT-11, Cosmegen CPT-11, Cytadren Cytadren R, @, Cytosar-U Cytosar-U ®, @, Cytoxan Cytoxan @, Dacarbazine, ®, Dacarbazine, Dacogen, Dacogen,

Dactinomycin, Darbepoetin Dactinomycin, Darbepoetin Alfa, Alfa, Dasatinib, Dasatinib, Daunomycin, DaunorubicinHydrochloride, Daunomycin, Daunorubicin Hydrochloride, Daunorubicin Liposomal, Daunorubicin Liposomal,DaunoXome DaunoXome @, Decadron, ®, Decadron, Decitabine, Decitabine, Delta-Cortef Delta-Cortef ®, @, Deltasone Deltasone R, @, Denileukin, Diftitox, Denileukin, Diftitox,DepoCyt TM,Dexamethasone, DepoCyt TM, DexamethasoneAcetate, Dexamethasone, Dexamethasone Acetate,Dexamethasone Dexamethasone SodiumPhosphate, Sodium Phosphate, Dexasone, Dexasone,Dexrazoxane, Dexrazoxane,DHAD, DHAD, DIC,DIC, Diodex, Diodex, Docetaxel, Docetaxel, Doxil Doxil ®, @, Doxorubicin, Doxorubicin Doxorubicin, Doxorubicin Liposomal, Liposomal, Droxia DroxiaTM, DTIC,DTIC-Dome TM, DTIC, DTIC-Dome @, Duralone ®, Duralone @, Efudex ®, Efudex

@, Eligard R, EligardTM, EllenceTM, TM,Ellence Eloxatin TM,Eloxatin TM,TM, Elspar Elspar @, Emcyt ®, Emcyt @, Epirubicin, ®, Epirubicin, EpoetinEpoetin Alfa, Erbitux, Alfa, Erbitux,

Erlotinib, Erwinia Erlotinib, L-asparaginase, Erwinia L-asparaginase, Estramustine, Estramustine, Ethyol, Ethyol, Etopophos Etopophos @, Etoposide, ®, Etoposide, Etoposide Etoposide

Phosphate, Eulexin Phosphate, Eulexin @, R, Everolimus, Everolimus, Evista Evista @, ®, Exemestane, Exemestane, Fareston Fareston @, R, Faslodex Faslodex @, R, Femara @, Femara R,

Filgrastim, Floxuridine, Filgrastim, Floxuridine,Fludara FludaraR, @, Fludarabine, Fludarabine, Fluoroplex Fluoroplex @, Fluorouracil, R, Fluorouracil, Fluorouracil Fluorouracil

(cream), Fluoxymesterone, (cream), Fluoxymesterone, Flutamide, Flutamide, Folinic Folinic Acid, Acid, FUDR FUDR ®, @, Fulvestrant, Fulvestrant, G-CSF, G-CSF, Gefitinib, Gefitinib, Gemcitabine, Gemtuzumab, Gemcitabine, Gemtuzumab,ozogamicin, ozogamicin, Gemzar Gemzar Gleevec Gleevec TM, TM, Gliadel Gliadel @ Wafer, R Wafer, GM-CSF, GM-CSF,

Goserelin, Granulocyte --Colony Goserelin, Granulocyte Colony Stimulating StimulatingFactor, Factor,Granulocyte GranulocyteMacrophage Macrophage Colony Colony

Stimulating Factor, Stimulating Factor,Halotestin Halotestin@,®,Herceptin Herceptin@,®,Hexadrol, Hexadrol,Hexalen Hexalen@,R, Hexamethylmelamine, Hexamethylmelamine,

HMM, HMM, Hycamtin Hycamtin ®, @, Hydrea Hydrea @, Hydrocort ®, Hydrocort Acetate Acetate @, Hydrocortisone, ®, Hydrocortisone, Hydrocortisone Hydrocortisone Sodium Sodium

Phosphate, Hydrocortisone Phosphate, SodiumSuccinate, Hydrocortisone Sodium Succinate, Hydrocortone HydrocortonePhosphate, Phosphate, Hydroxyurea, Hydroxyurea, Ibritumomab, Ibritumomab, Ibritumomab, Ibritumomab, Tiuxetan, Tiuxetan, Idamycin Idamycin @, Idarubicin R, Idarubicin Ifex @, IFN-alpha, Ifex R, IFN-alpha, Ifosfamide,Ifosfamide,

IL-11, IL-2, IL-11, IL-2, Imatinib Imatinibmesylate, mesylate,Imidazole Imidazole Carboxamide, Carboxamide, Interferon Interferon alfa, Interferon alfa, Interferon Alfa-2bAlfa-2b

(PEGConjugate), (PEG Conjugate), Interleukin-2, Interleukin-2, Interleukin-11, Interleukin-11, Intron Intron A@ (interferon AR (interferon alfa-2b), alfa-2b), Iressa Iressa R, @, Irinotecan, Isotretinoin, Irinotecan, Isotretinoin, Ixabepilone, Ixabepilone,Ixempra IxempraTM,TM, Kidrolase Kidrolase @, Lanacort ®, Lanacort @, Lapatinib, ®, Lapatinib, L- L asparaginase, LCR, asparaginase, LCR, Lenalidomide, Lenalidomide, Letrozole, Letrozole, Leucovorin, Leucovorin, Leukeran, Leukeran, Leukine Leukine TM, TM, Leuprolide, Leuprolide,

Leurocristine, Leustatin Leurocristine, LeustatinTM, Liposomal TM,Liposomal Ara-C, Ara-C, Liquid Liquid Pred Pred R, @, Lomustine, Lomustine, L-PAM, L-L-PAM, L Sarcolysin, Lupron Sarcolysin, Lupron @, R, Lupron Depot ®, Lupron Depot @, Matulane Matulane®,@,Maxidex, Maxidex,Mechlorethamine, Mechlorethamine, MechlorethamineHydrochloride, Mechlorethamine Hydrochloride,Medralone Medralone®,@,Medrol Medrol ®, @, Megace Megace @, Megestrol, ®, Megestrol, Megestrol Megestrol

Acetate, Melphalan, Acetate, Melphalan, Mercaptopurine, Mercaptopurine, Mesna, MesnexTM, Mesna, Mesnex Methotrexate, Methotrexate TM,Methotrexate, Methotrexate Sodium, Sodium, Methylprednisolone, Meticorten Methylprednisolone, Meticorten ®, @, Mitomycin, Mitomycin, Mitomycin-C, Mitomycin-C,Mitoxantrone, Mitoxantrone,M-Prednisol M-PrednisolR,@, MTC,MTX, MTC, MTX, Mustargen Mustargen @, Mustine, ®, Mustine, Mutamycin Mutamycin @, Myleran ®, Myleran @, Mylocel R, Mylocel TM, Mylotarg TM, Mylotarg ®, @,

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Navelbine @, Nelarabine, Navelbine R, Nelarabine, Neosar @, Neulasta Neosar ®, TM, TM, Neumega @,Neupogen Neumega R, Neupogen®, @, Nexavar Nexavar ®, @, 2023206094 18 Jul 2023

Nilandron @, Nilotinib, Nilandron ®, Nilotinib, Nilutamide, Nilutamide,Nipent Nipent@,R,Nitrogen NitrogenMustard, Mustard,Novaldex Novaldex @, ®, Novantrone Novantrone @, ®,

Nplate, Nplate, Octreotide, Octreotide,Octreotide Octreotideacetate, Ofatumumab, acetate, Ofatumumab,Oncospar Oncospar @, ®, Oncovin Oncovin @, ®, Ontak Ontak @, Onxal R, Onxal

TM, Oprelvekin,Orapred TM, Oprelvekin, Orapred @, Orasone R, Orasone @, Oxaliplatin, ®, Oxaliplatin, Paclitaxel, Paclitaxel, Paclitaxel Paclitaxel Protein-bound, Protein-bound,

Pamidronate,Panitumumab, Pamidronate, Panitumumab, Panretin Panretin @, Paraplatin ®, Paraplatin @, Pazopanib, ®, Pazopanib, PediapredPediapred @, PEG ®, PEG Interferon, Interferon, Pegaspargase, Pegfilgrastim, Pegaspargase, Pegfilgrastim,PEG-INTRON PEG-INTRON TM,TM, PEG-L-asparaginase, PEG-L-asparaginase, PEMETREXED, PEMETREXED,

Pentostatin, Phenylalanine Pentostatin, PhenylalanineMustard, Mustard, Platinol Platinol @, Platinol-AQ ®, Platinol-AQ @, Prednisolone, R, Prednisolone, Prednisone, Prednisone,

Prelone @, Prelone R, Procarbazine, Procarbazine, PROCRIT PROCRIT R,@,Proleukin Proleukin®,@,Prolifeprospan Prolifeprospan2020with with Carmustine Carmustine Implant, Purinethol Implant, Purinethol@, R,Raloxifene, Raloxifene,Revlimid Revlimid@,R,Rheumatrex Rheumatrex @, ®, Rituxan Rituxan @, ®, Rituximab, Rituximab, Roferon Roferon-

A R@(Interferon A (Interferon Alfa-2a), Alfa-2a),Romiplostim, Romiplostim,Rubex Rubex @, ®, Rubidomycin hydrochloride, Sandostatin Rubidomycin hydrochloride, Sandostatin R, @, Sandostatin LAR Sandostatin @,Sargramostim, LAR R, Sargramostim,Solu-Cortef Solu-Cortef®,@, Solu-Medrol Solu-MedrolR,@,Sorafenib, Sorafenib, SPRYCEL SPRYCELTM, TM,

STI-571,Streptozocin, STI-571, Streptozocin,SU11248, SUl1248, Sunitinib, Sunitinib, SutentSutent @, Tamoxifen, ®, Tamoxifen, Tarceva Tarceva ®, @, Targretin Targretin R, @, Tasigna ®, Tasigna @, Taxol Taxol R, @, Taxotere Taxotere ®, @, Temodar @,Temozolomide, Temodar R, Temozolomide, Temsirolimus, Temsirolimus, Teniposide, Teniposide,

TESPA,Thalidomide, TESPA, Thalidomide,Thalomid Thalomid ®, @, TheraCys TheraCys @, Thioguanine, ®, Thioguanine, Thioguanine Thioguanine Tabloid Tabloid R, @, Thiophosphoamide,Thioplex Thiophosphoamide, Thioplex®,@,Thiotepa, Thiotepa,TICE TICE®,@,Toposar Toposar R, @, Topotecan,Toremifene, Topotecan, Toremifene, Torisel Torisel

@, Tositumomab, R, Tositumomab,Trastuzumab, Trastuzumab,Treanda Treanda ®, @, Tretinoin, Trexall Tretinoin, Trexall TM, TM, Trisenox Trisenox @, ®, TSPA, TYKERB TSPA, TYKERB

@, VCR, R, VCR,Vectibix VectibixTM, Velban ®, TM, Velban @, Velcade VelcadeR,@, VePesid VePesid®,@,Vesanoid VesanoidR,@,Viadur ViadurTM, VidazaR,@, TM,Vidaza

Vinblastine, Vinblastine Vinblastine, VinblastineSulfate, Sulfate,Vincasar Vincasar Pfs Pfs @, Vincristine, R, Vincristine, Vinorelbine, Vinorelbine, Vinorelbine Vinorelbine tartrate, tartrate,

VLB,VM-26, VLB, VM-26, Vorinostat,Votrient, Vorinostat, Votrient, VP-16, VP-16, Vumon Vumon®, @, Xeloda Xeloda ®, @, Zanosar Zanosar ®, @, Zevalin Zevalin TM,TM,

Zinecard®,@,Zoladex Zinecard Zoladex @, Zoledronic R, Zoledronic acid, acid, Zolinza, Zolinza, ZometaZometa @, or combinations ®, or combinations of any of of theany of the above. above.

In certain

[0396] In certain

[0396] embodiments, embodiments, a provided a provided compound compound or composition may may or composition be administered be administered

together with together witha abiguanide biguanideselected selected from from metformin, metformin, phenformin, phenformin, or buformin, or buformin, to a patient to a patient in in needthereof. need thereof. InIncertain certainembodiments, embodiments, the patient the patient administered administered a combination a combination of a provided of a provided

compound compound andand a biguanide a biguanide is suffering is suffering from from a cancer, a cancer, obesity, obesity, a liver a liver disease, disease, diabetes diabetes or twoor ortwo or moreofofthe more theabove. above. In some

[0397] In some

[0397] embodiments, embodiments, a provided a provided compound compound or composition may bemay or composition be administered administered

together alone together aloneororwith withone oneorormore more additional additional therapeutic therapeutic agents agents for treatment for the the treatment of of acne acne vulgaris. In vulgaris. In some someembodiments, embodiments, theorone the one or additional more more additional therapeutic therapeutic agents agents for for the treatment the treatment

of acne of vulgaris are acne vulgaris areselected selectedfrom fromtopical topicalanti-acne anti-acne agents agents (e.g. (e.g. retinoids,topical retinoids, topicalantibiotics, antibiotics, benzoylperoxides), benzoyl peroxides),ororsystemic systemic anti-acne anti-acne agents agents (e.g. (e.g. hormonal hormonal therapies, therapies, oral antibiotics, oral antibiotics,

isotretinoin). In isotretinoin). In some someembodiments, embodiments, the hormonal the hormonal therapy therapy is ancontraceptive is an oral oral contraceptive or an or an androgenblocker. androgen blocker.In In some some embodiments, embodiments, theantibiotic the oral oral antibiotic is doxycycline, is doxycycline, minocycline, minocycline,

tetracycline, or tetracycline, erythromycin. or erythromycin.

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In some

[0398] In some

[0398] embodiments, embodiments, a provided a provided compound compound or composition may bemay or composition be administered administered 2023206094 18 Jul 2023

together alone together aloneororwith withone oneorormore more additional additional therapeutic therapeutic agents agents for treatment for the the treatment of seborrhea. of seborrhea.

In some In embodiments,aa provided some embodiments, provided compound compoundoror compositionmay composition may be be administeredtogether administered together alone or alone or with withone oneorormore more additional additional therapeutic therapeutic agents agents for the for the treatment treatment of seborrheic of seborrheic

dermatitis. InInsome dermatitis. some embodiments, embodiments, aa provided provided compound compound ororcomposition compositionmay maybebeadministered administered together alone together aloneororwith withone oneorormore more additional additional therapeutic therapeutic agents agents for treatment for the the treatment of seborrheic of seborrheic

keratosis. keratosis.

[0399] In certain

[0399] In certain embodiments, embodiments, a combination a combination of of twotwo or or more more therapeuticagents therapeutic agentsmay maybebe administeredtogether administered togetherwith with a provided a provided compound. compound. In certain In certain embodiments, embodiments, a combination a combination of 3 of 3 or more or therapeuticagents more therapeutic agents maymay be administered be administered with awith a provided provided compound. compound.

[0400] Other

[0400] Other examples examples of agents thethe of agents compounds compounds of this of this inventionmaymay invention also combined alsobebecombined with include, with include, without withoutlimitation: limitation:vitamins vitaminsandand nutritional nutritional supplements, supplements, cancer cancer vaccines, vaccines,

treatmentsfor treatments forneutropenia neutropenia(e.g. (e.g.G-CSF, G-CSF, filgrastim, filgrastim, lenograstim), lenograstim), treatments treatments for for thrombocytopenia thrombocytopenia (e.g. (e.g. blood blood transfusion, transfusion, erythropoietin), erythropoietin), P13 kinase PI3 kinase (PI3K)(P13K) inhibitors, inhibitors, MEK MEK inhibitors, AMPK inhibitors, activators, AMPK activators, PCSK9 PCSK9 inhibitors, inhibitors, SREBP SREBP site 1 protease site 1 protease inhibitors, inhibitors, HMG CoA-HMG CoA reductaseinhibitors, reductase inhibitors, antiemetics antiemetics(e.g. (e.g. 5-HT 5-HT3 receptor receptor antagonists, antagonists, dopamine dopamine antagonists, antagonists, NK1 NK1 receptor antagonists, receptor antagonists,histamine histaminereceptor receptor antagonists, antagonists, cannabinoids, cannabinoids, benzodiazepines, benzodiazepines, or or anticholinergics), treatments anticholinergics), treatmentsfor forAlzheimer's Alzheimer's Disease Disease such such as Aricept* as Aricept and Excelon*; and Excelon; treatmentstreatments

for Parkinson's for Diseasesuch Parkinson's Disease such as as L-DOPA/carbidopa, L-DOPA/carbidopa, entacapone, entacapone, ropinrole, ropinrole, pramipexole, pramipexole,

bromocriptine,pergolide, bromocriptine, pergolide,trihexephendyl, trihexephendyl, and and amantadine; amantadine; agentsagents for treating for treating Multiple Multiple Sclerosis Sclerosis

(MS)such (MS) suchasasbeta betainterferon interferon (e.g.,Avonex® (e.g., Avonex©and and Rebif*), Rebif®), Copaxone*, Copaxone®, and mitoxantrone; and mitoxantrone;

treatments for treatments forasthma asthmasuch such as as albuterol albuterol andand Singulair*; Singulair; agents agents for treating for treating schizophrenia schizophrenia such assuch as zyprexa, risperdal, zyprexa, risperdal, seroquel, seroquel, and andhaloperidol; haloperidol;anti-inflammatory anti-inflammatory agents agents such such as as corticosteroids, corticosteroids,

TNFblockers, TNF blockers, IL-1 IL- IRA, azathioprine, cyclophosphamide, RA, azathioprine, and sulfasalazine; cyclophosphamide, and sulfasalazine; immunomodulatory immunomodulatory

and immunosuppressive and immunosuppressiveagents agentssuch suchasas cyclosporin, cyclosporin, tacrolimus, tacrolimus,rapamycin, rapamycin,mycophenolate mycophenolate

mofetil, interferons, mofetil, interferons, corticosteroids, corticosteroids, cyclophophamide, cyclophophamide, azathioprine, azathioprine, and sulfasalazine; and sulfasalazine;

neurotrophicfactors neurotrophic factorssuch suchasasacetylcholinesterase acetylcholinesterase inhibitors, inhibitors, MAOMAO inhibitors, inhibitors, interferons, interferons, anti- anti convulsants, ion convulsants, ionchannel channelblockers, blockers, riluzole,andand riluzole, anti-Parkinsonian anti-Parkinsonian agents; agents; agents agents for treating for treating

cardiovasculardisease cardiovascular diseasesuch such as as beta-blockers, beta-blockers, ACE ACE inhibitors, inhibitors, diuretics, diuretics, nitrates, nitrates, calcium calcium channel channel

blockers, and blockers, andstatins, statins, fibrates, fibrates, cholesterol absorptioninhibitors, cholesterol absorption inhibitors, bile bile acid acid sequestrants, sequestrants, and and niacin; agents niacin; for treating agents for treating liver liver disease such asascorticosteroids, disease such corticosteroids, cholestyramine, cholestyramine, interferons, interferons, andand

anti-viral agents; anti-viral agents; agents for treating agents for treating blood blooddisorders disorderssuch suchasascorticosteroids, corticosteroids,anti-leukemic anti-leukemic agents, and agents, and growth growthfactors; factors;agents agents forfor treatingimmunodeficiency treating immunodeficiency disorders disorders such assuch as gamma gamma globulin; and globulin; andanti-diabetic anti-diabeticagents agentssuch such as as biguanides biguanides (metformin, (metformin, phenformin, phenformin, buformin), buformin),

thiazolidinediones(rosiglitazone, thiazolidinediones (rosiglitazone,pioglitazone, pioglitazone,troglitazone), troglitazone),sulfonylureas sulfonylureas (tolbutamide, (tolbutamide,

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acetohexamide,tolazamide, acetohexamide, tolazamide, chlorpropamide, chlorpropamide, glipizide, glipizide, glyburide, glyburide, glimepiride, glimepiride, gliclazide), gliclazide), 2023206094 18 Jul 2023

meglitinides(repaglinide, meglitinides (repaglinide,nateglinide), nateglinide),alpha-glucosidase alpha-glucosidase inhibitors inhibitors (miglitol, (miglitol, acarbose), acarbose), incretin incretin

mimetics(exenatide, mimetics (exenatide,liraglutide, liraglutide,taspoglutide), taspoglutide),gastric gastricinhibitory inhibitorypeptide peptide analogs, analogs, DPP-4 DPP-4

inhibitors (vildagliptin, inhibitors (vildagliptin, sitagliptin, sitagliptin,saxagliptin, saxagliptin,linagliptin, linagliptin,alogliptin), amylin alogliptin), amylin analogs analogs

(pramlintide), and (pramlintide), andinsulin insulinand andinsulin insulinanalogs. analogs. In certain

[0401] In certain

[0401] embodiments, embodiments, a provided a provided compound, or aorpharmaceutically compound, a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,areareadministered administered in combination in combination with antisense with antisense agents,agents, a monoclonal a monoclonal or or polyclonalantibody polyclonal antibodyor or a siRNA a siRNA therapeutic. therapeutic.

[0402] In some

[0402] In some embodiments, embodiments, the present the present invention invention provides provides a method a method of of treating, treating,

stabilizing or stabilizing or lessening the severity lessening the severity or or progression progressionofofa anon-alcoholic non-alcoholic fatty fatty liverdisease liver disease (NAFLD), (NAFLD), comprising comprising administering administering to a patient to a patient in thereof in need need thereof a provided a provided compound, compound, or a or a pharmaceuticallyacceptable pharmaceutically acceptable composition composition thereof, thereof, in combination in combination with with one one additional or more or more additional therapeutic agents. therapeutic agents. InIncertain certainembodiments, embodiments, the or the one onemore or more additional additional therapeutic therapeutic agents agents are are independentlyselected independently selectedfrom from thethe group group consisting consisting of angiotensin of angiotensin II receptor II receptor antagonists, antagonists,

angiotensinconverting angiotensin convertingenzyme enzyme (ACE)(ACE) inhibitors, inhibitors, caspase caspase inhibitors, inhibitors, cathepsin cathepsin B inhibitors, B inhibitors,

CCR2chemokine CCR2 chemokine antagonists,CCR5 antagonists, CCR5 chemokine chemokine antagonists, antagonists, chloridechannel chloride channelstimulators, stimulators, cholesterol solubilizers, cholesterol solubilizers, diacylglycerol diacylglycerolO-acyltransferase 0-acyltransferase 1 (DGATl) 1 (DGAT1) inhibitors, inhibitors, dipeptidyl dipeptidyl

peptidase IV peptidase IV (DPPIV) inhibitors, farnesoid (DPPIV) inhibitors, farnesoidX Xreceptor (FXR) receptor (FXR)agonists, agonists,FXR/TGR5 dual FXR/TGR5 dual

agonists, galectin-3 agonists, galectin-3 inhibitors, inhibitors, glucagon-like glucagon-likepeptide peptide 1 (GLP1) 1 (GLP1) agonists, agonists, glutathione glutathione precursors, precursors,

hepatitis C hepatitis virus NS3 C virus NS3protease protease inhibitors,HMGHMG inhibitors, CoA reductase CoA reductase inhibitors, inhibitors, 11p-hydroxysteroid 11-hydroxysteroid

dehydrogenase dehydrogenase (11p-HSD1) (11ß-HSD1) inhibitors, inhibitors, IL- Iantagonists, IL-1 antagonists, IL-6 antagonists, IL-6 antagonists, IL-10 agonists, IL-10 agonists, IL- IL 17 antagonists, 17 antagonists, ileal ileal sodium sodiumbile bileacid acidcotransporter cotransporterinhibitors, inhibitors,leptin leptinanalogs, analogs,5-lipoxygenase 5-lipoxygenase inhibitors, LPL inhibitors, genestimulators, LPL gene stimulators,lysyl lysyloxidase oxidase homolog homolog 2 (LOXL2) 2 (LOXL2) inhibitors, inhibitors, PDE3 inhibitors, PDE3 inhibitors,

PDE4inhibitors, PDE4 inhibitors, phospholipase phospholipase C C (PLC) inhibitors, PPARa (PLC) inhibitors, agonists, PPARy PPAR agonists, agonists,PPAR PPAR agonists, PPAR agonists, Rho agonists, Rhoassociated associatedprotein protein kinase kinase 2 (ROCK2) 2 (ROCK2) inhibitors, inhibitors, sodiumsodium glucose glucose transporter-2 transporter-2

(SGLT2) (SGLT2) inhibitors,stearoyl inhibitors, stearoyl CoACoA desaturase-1 desaturase-1 inhibitors, inhibitors, thyroid thyroid hormone hormone receptorreceptor P ß agonists,agonists,

tumornecrosis tumor necrosisfactor factor (TNF) a (TNFa) ligandligand inhibitors, inhibitors, transglutaminase transglutaminase inhibitors, inhibitors, transglutaminase transglutaminase

inhibitor precursors, inhibitor PTPlb precursors, PTP1b inhibitors,andand inhibitors, ASK ASK1 Iinhibitors. inhibitors.

In some

[0403] In some

[0403] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is an an angiotensin angiotensin II II receptor receptor

antagonist. antagonist.

In some

[0404] In some

[0404] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

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agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is an an angiotensin angiotensin converting converting 2023206094 18 Jul 2023

enzyme(ACE) enzyme (ACE) inhibitor. inhibitor. In some In some embodiments, embodiments, the ACE is the ACE inhibitor inhibitor is enalapril. enalapril.

In some

[0405] In some

[0405] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a caspase a caspase inhibitor. inhibitor. In some In some

embodiments embodiments the the caspase caspase inhibitor inhibitor is emricasan. is emricasan.

In some

[0406] In some

[0406] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a cathepsin a cathepsin B inhibitor. B inhibitor. In In someembodiments some embodiments the cathepsin the cathepsin B inhibitor B inhibitor is a mixed is a mixed cathepsin cathepsin B/hepatitis B/hepatitis C virus C virus NS3 NS3 protease inhibitor. protease inhibitor. InInsome some embodiments, embodiments, the mixed the mixed cathepsin cathepsin B/hepatitis B/hepatitis C virus C virus NS3 NS3 protease protease inhibitor is inhibitor is VBY-376. VBY-376.

In some

[0407] In some

[0407] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a CCR2 a CCR2 chemokine chemokine

antagonist. In antagonist. In some some embodiments, the additional embodiments, the additionaltherapeutic agent therapeutic is aismixed agent CCR2/CCR5 a mixed CCR2/CCR5

chemokineantagonist. chemokine antagonist. In In some some embodiments, embodiments,the themixed mixedCCR2/CCR5 CCR2/CCR5 chemokine chemokine antagonist antagonist is is cenicriviroc. cenicriviroc.

In some

[0408] In some

[0408] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a CCR5 a CCR5 chemokine chemokine

antagonist. antagonist.

In some

[0409] In some

[0409] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a chloride a chloride channel channel stimulator. stimulator.

In some In embodiments, some embodiments, the chloride the chloride channel channel stimulator stimulator is cobiprostone. is cobiprostone.

In some

[0410] In some

[0410] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a cholesterol a cholesterol solubilizer. solubilizer.

In some

[0411] In some

[0411] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a diacylglycerol a diacylglycerol 0- 0 acyltransferase 11(DGATl) acyltransferase inhibitor. In (DGAT1) inhibitor. Insome some embodiments, the DGATl embodiments, the inhibitor is DGAT1 inhibitor is LCQ908. LCQ908.

In some

[0412] In some

[0412] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

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agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a dipeptidyl a dipeptidyl peptidase peptidase IV IV 2023206094 18 Jul 2023

(DPPIV)inhibitor. (DPPIV) inhibitor.In In some some embodiments, embodiments, the inhibitor the DPPIV DPPIV inhibitor is linagliptin. is linagliptin.

In some In embodiments,aa provided some embodiments, provided compound, compound,orora apharmaceutically pharmaceutically acceptable acceptable composition composition thereof, is thereof, is administered incombination administered in combination with with one one or more or more additional additional therapeutic therapeutic agents, agents, whereinwherein

at least at least one one of of the the additional therapeutic agents additional therapeutic agentsisis aa farnesoid farnesoidX Xreceptor receptor (FXR) (FXR) agonist. agonist. In In some embodiments, some embodiments,the theFXR FXR agonistisis INT-747 agonist INT-747(obeticholic (obeticholic acid). acid). In In some some embodiments, the embodiments, the

FXRagonist FXR agonist is is PX-102. PX-102.

In some

[0413] In some

[0413] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is an an FXR/TGR5 FXR/TGR5 dual agonist. dual agonist.

In some In embodiments,the some embodiments, the FXR/TGR5 FXR/TGR5 dual dual agonist agonist is isINT-767. INT-767. In some

[0414] In some

[0414] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a galectin-3 a galectin-3 inhibitor.In In inhibitor. some some

embodiments, embodiments, thethe galectin-3 galectin-3 inhibitor inhibitor is GR-MD-02. is GR-MD-02.

In some

[0415] In some

[0415] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a glucagon-like a glucagon-like peptide peptide 1 1 (GLP1)agonist. (GLP1) agonist. In In some some embodiments, embodiments,the theGLP1 GLP1agonist agonistisis liraglutide. liraglutide.In Insome some embodiments, embodiments,

the GLP1 the agonist GLP1 agonist is is exenatide. exenatide.

In some

[0416] In some

[0416] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a glutathione a glutathione precursor. precursor.

In some

[0417] In some

[0417] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a hepatitisC C a hepatitis virus virus NS3NS3

protease inhibitor. protease inhibitor. InInsome some embodiments embodiments the heptatitis the heptatitis C virus C virus NS3 protease NS3 protease inhibitor inhibitor is a is a mixedcathepsin mixed cathepsin B/hepatitis B/hepatitis C virus C virus NS3NS3 protease protease inhibitor. inhibitor. In embodiments, In some some embodiments, the mixed the mixed cathepsin B/hepatitis cathepsin B/hepatitisC Cvirus virusNS3 NS3 protease protease inhibitor inhibitor is VBY-376. is VBY-376.

In some

[0418] In some

[0418] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is an an HMGHMG CoA reductase CoA reductase

inhibitor. In inhibitor. In some someembodiments, embodiments, the HMG-CoA the HMG-CoA reductase reductase inhibitor inhibitor is is aInstatin. a statin. some In some embodiments, embodiments, thethe HMG-CoA HMG-CoA reductase reductase inhibitorinhibitor is atorvastatin. is atorvastatin.

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In some

[0419] In some

[0419] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable 2023206094 18 Jul 2023

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is an an11p-hydroxysteroid 11ß-hydroxysteroid

dehydrogenase (11ß-HSD1) dehydrogenase (11p-HSD1)inhibitor. inhibitor. InIn some someembodiments, embodiments,thethe11ß-HSD1 11p-HSD1 inhibitorisis inhibitor

R05093151. RO5093151.

In some

[0420] In some

[0420] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is an an IL-Iantagonist. IL-1ß antagonist.

[0421]

[0421] In some In embodiments,aaprovided some embodiments, compound,orora apharmaceutically provided compound, acceptable pharmaceutically acceptable compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is an an IL-6 IL-6 antagonist. antagonist. In some In some

embodiments, the embodiments, the IL-6 IL-6 antagonist antagonist isisa amixed mixedIL-6/IL-1 /TNFa IL-6/IL-1/TNF ligandinhibitor. ligand inhibitor. In In some some

embodiments, the embodiments, the mixed mixedIL-6/IL-1/TNF IL-6/IL-1 /TNFa ligand ligand inhibitor inhibitor is isBLX-1002. BLX-1002. In some

[0422] In some

[0422] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is an an IL-10 IL-10 agonist. agonist. In some In some

embodiments, embodiments, thethe IL-10 IL-10 agonist agonist is peg-ilodecakin. is peg-ilodecakin.

In some

[0423] In some

[0423] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is an an IL-17 IL-17 antagonist. antagonist. In some In some

embodiments, embodiments, thethe IL-17 IL-17 antagonist antagonist is KD-025. is KD-025.

In some

[0424] In some

[0424] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is an an ilealsodium ileal sodium bilebile acidacid

cotransporter inhibitor. cotransporter inhibitor. InInsome some embodiments, embodiments, the ileal the ileal sodium sodium bile cotransporter bile acid acid cotransporter inhibitor inhibitor

is SHP-626. is SHP-626.

In some

[0425] In some

[0425] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a leptinanalog. a leptin analog.In some In some embodiments embodiments the the leptin leptin analog analog is metreleptin. is metreleptin.

In some

[0426] In some

[0426] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a 5-lipoxygenase a 5-lipoxygenase inhibitor. inhibitor. In In some embodiments, some embodiments,the the5-lipoxygenase 5-lipoxygenase inhibitor inhibitor isisa amixed mixed5-lipoxygenase/PDE3/PDE4/PLC 5-lipoxygenase/PDE3/PDE4/PLC

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inhibitor. InInsome inhibitor. someembodiments, embodiments, the the mixed mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitorisis 5-lipoxygenase/PDE3/PDE4/PLC inhibitor 2023206094 18 Jul 2023

tipelukast. tipelukast.

In some

[0427] In some

[0427] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a LPL a LPL genegene stimulator. stimulator. In In someembodiments some embodiments the gene the LPL LPLstimulator gene stimulator is alipogene is alipogene tiparvovec. tiparvovec.

In some

[0428] In some

[0428] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a lysyloxidase a lysyl oxidase homolog homolog 2 2 (LOXL2)inhibitor. (LOXL2) inhibitor. In In some some embodiments, embodiments,the theLOXL2 LOXL2 inhibitorisisan inhibitor an anti-LOXL2 anti-LOXL2antibody. antibody.InIn some embodiments, some embodiments,the theanti-LOXL2 anti-LOXL2 antibody antibody is isGS-6624. GS-6624. In some

[0429] In some

[0429] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a PDE3 a PDE3 inhibitor. inhibitor. In some In some

embodiments, the embodiments, the PDE3 PDE3inhibitor inhibitor is is aa mixed mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor.InIn 5-lipoxygenase/PDE3/PDE4/PLC inhibitor.

some embodiments, some embodiments,the themixed mixed5-lipoxygenase/PDE3/PDE4/PLC 5-lipoxygenase/PDE3/PDE4/PLC inhibitor inhibitor is tipelukast. is tipelukast.

In some

[0430] In some

[0430] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a PDE4 a PDE4 inhibitor. inhibitor. In some In some

embodiments, the embodiments, the PDE4 PDE4inhibitor inhibitor is is ASP-9831. In some ASP-9831. In someembodiments, embodiments,thethePDE4 PDE4 inhibitorisis aa inhibitor

mixed 5-lipoxygenase/PDE3/PDE4/PLC mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitor. inhibitor. In In some some embodiments, embodiments, the the mixed mixed 5- 5 lipoxygenase/PDE3/PDE4/PLC lipoxygenase/PDE3/PDE4/PLC inhibitor inhibitor is tipelukast. is tipelukast.

In some

[0431] In some

[0431] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a phospholipase a phospholipase C (PLC) C (PLC)

inhibitor. InInsome inhibitor. someembodiments, embodiments, the the PLC inhibitor isisa mixed PLC inhibitor a mixed5-lipoxygenase/PDE3/PDE4/PLC 5-lipoxygenase/PDE3/PDE4/PLC

inhibitor. InInsome inhibitor. someembodiments, embodiments, the the mixed mixed 5-lipoxygenase/PDE3/PDE4/PLC inhibitorisis 5-lipoxygenase/PDE3/PDE4/PLC inhibitor

tipelukast. tipelukast.

In some

[0432] In some

[0432] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a PPARa a PPAR agonist. agonist. In someIn some embodimentsthe embodiments thePPAR PPARa agonist agonist is is a mixed a mixed PPARa/6 PPAR/ agonist. agonist. In some In some embodiments, embodiments, the the mixed PPARa/6 mixed agonistis PPAR/ agonist is GFT505. GFT505.

[0433]

[0433] In In some embodiments,aaprovided some embodiments, compound,orora apharmaceutically provided compound, acceptable pharmaceutically acceptable compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone oradditional more more additional therapeutic therapeutic

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agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a PPARy a PPARy agonist. agonist. In In some some 2023206094 18 Jul 2023

embodiments, the embodiments, the PPAR PPARy agonist agonist is ispioglitazone. pioglitazone. In some

[0434] In some

[0434] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a PPAR a PPAR agonist. agonist.

In some

[0435] In some

[0435] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a Rho a Rho associated associated protein protein

kinase 22 (ROCK2) kinase inhibitor. In (ROCK2) inhibitor. In some embodimentsthe some embodiments theROCK2 ROCK2 inhibitor inhibitor isisKD-025. KD-025. In some

[0436] In some

[0436] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a sodium a sodium glucose glucose transporter transporter-

2 (SGLT2) 2 (SGLT2) inhibitor.In In inhibitor. some some embodiments, embodiments, theinhibitor the SGLT2 SGLT2 inhibitor is remogliflozin is remogliflozin etabonate. etabonate.

In some

[0437] In some

[0437] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a stearoyl a stearoyl CoACoA desaturase-1 desaturase-1

inhibitor. In inhibitor. In some someembodiments, embodiments, the stearoyl the stearoyl CoA desaturase-1 CoA desaturase-1 inhibitor inhibitor is aramchol. is aramchol. In some In some embodiments, embodiments, thethe stearoyl stearoyl CoA CoA desaturase-1 desaturase-1 inhibitor inhibitor is CVT-12805. is CVT-12805.

In some

[0438] In some

[0438] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a thyroid a thyroid hormone hormone receptors receptor ß

agonist. In agonist. In some some embodiments the thyroid embodiments the thyroid hormone P receptor ß agonist hormone receptor agonist isisMGL-3196. MGL-3196.

In some

[0439] In some

[0439] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a tumor a tumor necrosis necrosis factor factor a (TNFa) (TNF) ligand ligand inhibitor. inhibitor.

In some

[0440] In some

[0440] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a transglutaminase a transglutaminase inhibitor. inhibitor.

In some In embodiments, some embodiments, the transglutaminase the transglutaminase inhibitor inhibitor precursor precursor is mercaptamine. is mercaptamine.

[0441]

[0441] In some embodiments,aaprovided some embodiments, compound,orora apharmaceutically provided compound, acceptable pharmaceutically acceptable compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a transglutaminase a transglutaminase inhibitor inhibitor

precursor. precursor.

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In some

[0442] In some

[0442] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable 2023206094 18 Jul 2023

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is a PTPlb a PTP1b inhibitor. inhibitor. In some In some

embodiments, the embodiments, the PTP1b PTPlbinhibitor inhibitor is is A119505, A220435,A321842, A119505, A220435, A321842,CPT633, CPT633, ISIS-404173, ISIS-404173,

JTT-551, MX-7014, JTT-551, MX-7014, MX-7091, MX-7091, MX-7102, NNC-521246, OTX-001, MX-7102, NNC-521246, OTX-001, OTX-002, OTX-002,or or TTP814. TTP814. In some

[0443] In some

[0443] embodiments, embodiments, a provided a provided compound, compound, or a pharmaceutically or a pharmaceutically acceptable acceptable

compositionthereof, composition thereof,isisadministered administered in combination in combination with with one orone or additional more more additional therapeutic therapeutic

agents, wherein agents, whereinatatleast leastone oneofofthe theadditional additionaltherapeutic therapeuticagents agents is is an an ASKI ASK1 inhibitor. inhibitor. In In some some embodiments, embodiments, thethe ASKI ASK1 inhibitor inhibitor is GS-4977 is GS-4977 (alsoasknown (also known as selonsertib). selonsertib).

In some

[0444] In some

[0444] embodiments, embodiments, the one or more onemore the or additional additional therapeutic are agentsare therapeuticagents independentlyselected independently selected from from acetylsalicylic acetylsalicylic acid, acid, alipogene alipogene tiparvovec, tiparvovec, aramchol, aramchol, atorvastatin, atorvastatin,

BLX-1002,cenicriviroc, BLX-1002, cenicriviroc, cobiprostone, cobiprostone, colesevelam, colesevelam, emricasan, emricasan,enalapril, enalapril,GFT-505, GR-MD GFT-505, GR-MD-

02, hydrochlorothiazide, 02, hydrochlorothiazide,icosapent icosapent ethyl ethyl ester ester (ethyl (ethyl eicosapentaenoic eicosapentaenoic acid), acid), IMM-124E, IMM-124E, KD- KD 025, linagliptin, 025, linagliptin, liraglutide, liraglutide, mercaptamine, MGL-3196, mercaptamine, MGL-3196, obeticholic obeticholic acid, acid, olesoxime, olesoxime, peg- peg ilodecakin, pioglitazone, ilodecakin, pioglitazone,PX-102, PX-102, remogliflozin remogliflozin etabonate, etabonate, SHP-626, SHP-626, solithromycin, solithromycin, tipelukast, tipelukast,

TRX-318,ursodeoxycholic TRX-318, ursodeoxycholicacid, acid, and and VBY-376. VBY-376.

[0445] In some

[0445] In some embodiments, embodiments, onethe one of one one of the or more or more additional additional therapeutic agentsisis therapeuticagents acetylsalicylic acid. acetylsalicylic acid. In In some someembodiments, embodiments, one one of theofone theorone or additional more more additional therapeutic therapeutic agents agents is alipogene is tiparvovec.InInsome alipogene tiparvovec. some embodiments, embodiments, one ofone the of onethe or one more or more additional additional therapeutic therapeutic

agents isis aramchol. agents aramchol.InInsome some embodiments, embodiments, one of one the of onethe or one more or more additional additional therapeutic therapeutic agents agents is atorvastatin. is atorvastatin. In some someembodiments, embodiments, onetheofone one of the or one or additional more more additional therapeutic therapeutic agents agents is is BLX-1002. BLX-1002. In some In some embodiments, embodiments, oneone one of the of or themore oneadditional or more additional therapeutictherapeutic agents is agents is cenicriviroc. InInsome cenicriviroc. someembodiments, embodiments, one one of theof theorone one oradditional more more additional therapeutic therapeutic agents agents is is cobiprostone.In Insome cobiprostone. some embodiments, embodiments, one of one the of onethe or one moreor more additional additional therapeutic therapeutic agents is agents is colesevelam.In In colesevelam. some some embodiments, embodiments, one of one of the the one one or or more more additional additional therapeutic therapeutic agents is agents is emricasan.InInsome emricasan. some embodiments, embodiments, one ofone the of onethe or one more or more additional additional therapeutic therapeutic agents is agents is enalapril. In enalapril. In some someembodiments, embodiments, onetheofone one of theorone or additional more more additional therapeutic therapeutic agents agents is GFT- is GFT 505. InInsome 505. some embodiments, embodiments, one ofone theof theorone one moreoradditional more additional therapeutic therapeutic agents isagents is GR-MD-02. GR-MD-02.

In some In embodiments, some embodiments, onethe one of ofone the or onemore or more additional additional therapeutic therapeutic agents agents is is hydrochlorothiazide.In In hydrochlorothiazide. some some embodiments, embodiments, one of one of the the one one or or more more additional additional therapeutic therapeutic

agents isis icosapent agents icosapentethyl ethylester ester (ethyl (ethyl eicosapentaenoic eicosapentaenoic acid).In some acid). In some embodiments, embodiments, one one of the of the one or one or more moreadditional additionaltherapeutic therapeutic agents agents is IMM-124E. is IMM-124E. In someIn some embodiments, embodiments, one of the one one of the one or more or additionaltherapeutic more additional therapeuticagents agents is is KD-025. KD-025. In embodiments, In some some embodiments, one one of the oneof orthe one more or more additional therapeutic additional therapeuticagents agentsisislinagliptin. linagliptin. InInsome some embodiments, embodiments, one ofone theof theorone one moreor more additional therapeutic additional therapeuticagents agentsisisliraglutide. liraglutide. InInsome some embodiments, embodiments, one ofone theof theorone one moreor more

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additional therapeutic additional therapeuticagents agentsisismercaptamine. mercaptamine. In some In some embodiments, embodiments, oneoneoforthemore one of the one or more additional therapeutic therapeuticagents agentsisisMGL-3196. MGL-3196. In embodiments, some embodiments, one of theone oneof orthe one or more 18 Jul 2023

additional In some more

additional therapeutic additional therapeuticagents agentsisisobeticholic obeticholicacid. acid.In In some some embodiments, embodiments, one of one the of onethe or one more or more additional therapeutic additional therapeuticagents agentsisisolesoxime. olesoxime. In some In some embodiments, embodiments, one one one of the of the one or more or more additional therapeutic additional therapeuticagents agentsisispeg-ilodecakin. peg-ilodecakin.In some In some embodiments, embodiments, one one one of the of the one or more or more additional therapeutic additional therapeuticagents agentsisispioglitazone. pioglitazone.In In some some embodiments, embodiments, one of one of the the one or one more or more additional therapeutic additional therapeuticagents agentsisisPX-102. PX-102. In some In some embodiments, embodiments, oneone one of the of or themore one or more 2023206094

additional therapeutic additional therapeuticagents agentsisisremogliflozin remogliflozin etabonate. etabonate. In some In some embodiments, embodiments, oneone one of the of the one or more or additionaltherapeutic more additional therapeuticagents agents is is SHP-626. SHP-626. In some In some embodiments, embodiments, one one of the oneof orthe one or moreadditional more additionaltherapeutic therapeuticagents agents is is solithromycin. solithromycin. In some In some embodiments, embodiments, oneoneoforthe one of the one or moreadditional more additionaltherapeutic therapeuticagents agents is is tipelukast.In In tipelukast. some some embodiments, embodiments, one of one of the the one one or more or more additional therapeutic additional therapeuticagents agentsisisTRX-318. TRX-318. In some In some embodiments, embodiments, oneoneoforthemore one of the one or more additional therapeutic additional therapeuticagents agentsisisursodeoxycholic ursodeoxycholic acid. acid. In some In some embodiments, embodiments, oneoneofor one of the the one or moreadditional more additionaltherapeutic therapeuticagents agents is is andand VBY-376. VBY-376.

In some

[0446] In some

[0446] embodiments, embodiments, at least at least one oneoneoforthemore of the oneadditional therapeutictherapeutic or more additional agents is agents is an anti-diabetic an anti-diabetic agent. agent. InInsome some embodiments, embodiments, the anti-diabetic the anti-diabetic agent agent is an is an adenosine adenosine Ai receptor A1 receptor

agonist (e.g. agonist (e.g.adenosine, CCPA, adenosine, CCPA, CVT-3619, GR-190718),ananadenosine CVT-3619, GR-190718), adenosineA A2 receptorantagonist receptor antagonist (istradefylline, SCH-58261), (istradefylline, SCH-58261), an an aldose aldose reductase reductase inhibitor, inhibitor, an a-amylase an -amylase inhibitor inhibitor (e.g. (e.g. tendamistat, treastatin, tendamistat, treastatin, AL-3688), AL-3688), an an c-glucosidase -glucosidase inhibitor inhibitor (e.g. (e.g. acarbose, acarbose, camiglibose, camiglibose,

diposine, emiglitate, diposine, emiglitate, miglitol, miglitol, pradimicin-Q, pradimicin-Q,sarbostatin, sarbostatin,voglibose), voglibose), an amylin an amylin analog analog (e.g. (e.g.

AC164209andandpramlintide), AC164209 pramlintide), an an AMPK AMPK activator,a aß3-adrenergic activator, 3-adrenergic agonist agonist (e.g. (e.g. amibegron, amibegron, AZ AZ-

40140, CL-316,243, 40140, CL-316,243, KRP-204, KRP-204,L-742,791, L-742,791,L-796,568, L-796,568,LY-368,842, LY-368,842, LY-377,604, LY-377,604, mirabegron, mirabegron,

Ro40-2148, Ro 40-2148,solabegron, solabegron, SWR-0342SA), SWR-0342SA), a -ketoacyl-acyl a ß-ketoacyl-acyl carriersynthase carrier protein protein inhibitor, synthase inhibitor, a a biguanide (e.g. metformin, biguanide (e.g. metformin, buformin, buformin, phenformin), phenformin), a carnitine a carnitine palmitoyl palmitoyl transferase transferase inhibitor, inhibitor, a a DGAT-2 DGAT-2 inhibitor, inhibitor, a DPP-4 a DPP-4 inhibitor inhibitor (e.g.(e.g. alogliptin, alogliptin, anagliptin, anagliptin, dutogliptin, dutogliptin, gemigliptin, gemigliptin,

linagliptin, omarigliptin, saxagliptin, sitagliptin, teneligliptin, trelagliptin, and vildagliptin), an linagliptin, omarigliptin, saxagliptin, sitagliptin, teneligliptin, trelagliptin, and vildagliptin), an

ERNI ERN1 inhibitor,a fatty inhibitor, a fattyacid acidoxidation oxidation inhibitor,a fatty inhibitor, a fattyacid acidsynthase synthase (FAS) (FAS) inhibitor, inhibitor, an FGF21 an FGF21

derivative, aa fructose derivative, fructose 1,6-diphosphatase 1,6-diphosphatase inhibitor,a GLP1 inhibitor, a GLP1 agonist agonist (e.g.(e.g. albiglutide, albiglutide, dulaglutide, dulaglutide,

exenatide, liraglutide, exenatide, liraglutide, lixisenatide, lixisenatide, taspoglutide), taspoglutide), aa glucagon glucagonreceptor receptormodulator, modulator, a mixed a mixed

glucagonreceptor glucagon receptor/ /GLP-1 GLP-1 agonist agonist (e.g. (e.g. MAR-701, MAR-701, ZP2929), ZP2929), a glucokinase a glucokinase inhibitor inhibitor (e.g. (e.g. TTP-399, TTP-355, TTP-399, TTP-355, TTP-547, TTP-547,AZD1656, AZD1656, ARRY403, MK-0599, TAK-329, ARRY403, MK-0599, TAK-329,AZD5658, AZD5658,and and GKM-001),a aglycogen GKM-001), glycogenphosphorylase phosphorylaseinhibitor inhibitor (e.g. (e.g. GSK1362885), GSK1362885), a aGSK-3 GSK-3inhibitor, inhibitor, aa GPR119agonist GPR119 agonist (e.g. (e.g.MBX-2982, MBX-2982,GSK1292263, GSK1292263,APD597, APD597, PSN821), PSN821),a aGPBAR1 GPBAR1 (TGR5) (TGR5)

agonist (e.g. agonist (e.g.INT-777, INT-777,XL-475), XL-475),a aGPR39 modulator, aa GPR40 GPR39 modulator, agonist (e.g. GPR40 agonist (e.g. TAK-875), TAK-875), aa

GPR41modulator, GPR41 modulator,a aGPR43 GPR43 modulator, modulator, a GPR81 a GPR81 modulator, modulator, a GPR120 a GPR120 agonist, agonist, an HSL an HSL

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inhibitor, an inhibitor, an IKB inhibitor,an an I inhibitor, ILI-beta ILI-beta modulator, modulator, insulin insulin or anorinsulin an insulin analog analog (including, (including, but but not not 2023206094 18 Jul 2023

limited to, limited to, oral, oral, inhaled or injectable inhaled or formulationsthereof), injectable formulations thereof),insulin-like insulin-likegrowth growth factor(IGF-1) factor (IGF-1) or or an analog an analogthereof, thereof,ananinsulin insulinsecretagogue, secretagogue, a JNK a JNK inhibitor inhibitor (e.g. (e.g. CC-359), CC-359), a kappa a kappa opioid opioid

receptor modulator, receptor modulator,LY3084077, LY3084077, a Kvl.3 a Kvl.3 inhibitor inhibitor (e.g. (e.g. ChTX, ChTX, clofazmine, clofazmine, WIN-173173), WIN-173173), a a MAP4K4 MAP4K4 inhibitor,ananMC1 inhibitor, MCiororMC4agonist (e.g. afamelanotide, MC4 agonist (e.g. afamelanotide, BMS-470539, BMS-470539,bremelanotide, bremelanotide, MelanotanII,II,PF-00446687, Melanotan PF-00446687, PL-6983, PL-6983, setmelanotide, setmelanotide, andaTHIQ), and THIQ), a meglitinide meglitinide (e.g. (e.g. repaglinide, nateglinide, repaglinide, nateglinide, mitiglinide), mitiglinide), aa mineralocorticoid mineralocorticoid receptor receptor inhibitor, inhibitor, a monoacylglycerol a monoacylglycerol

0-acyltransferaseinhibitor, O-acyltransferase inhibitor,ananNF-kB NF-KB inhibitor, inhibitor, a nicotinic a nicotinic acid acid receptor receptor (HM74A) (HM74A) activator, activator, a a PDE-10inhibitor, PDE-10 inhibitor, aaPDHK2 inhibitor, aa PDHK4 PDHK2 inhibitor, inhibitor, aa PKC PDHK4 inhibitor, (including PKC-alpha, PKC (including PKC PKC-alpha, PKC-

beta, and beta, PKC-gamma) and PKC-gamma) inhibitor, inhibitor, a PPARc/y a PPAR/y dual agonist, dual agonist, a PTPlb (e.g. a PTP1b inhibitor inhibitor (e.g. trodusquemine),a retinol trodusquemine), a retinolbinding binding protein protein 4 inhibitor, 4 inhibitor, a serine a serine palmitoyl palmitoyl transferase transferase inhibitor, inhibitor, an an SGLT1 SGLT1 inhibitor inhibitor (e.g.GSK1614235), (e.g. GSK1614235), a SIRT-1 a SIRT-1 inhibitor inhibitor (e.g. resveratrol, (e.g. resveratrol, GSK2245840, GSK2245840,

GSK184072), GSK184072), a somatostatin a somatostatin receptor receptor inhibitor, inhibitor, a sulfonylurea a sulfonylurea (e.g. (e.g. acetohexamide, acetohexamide,

chlorpropamide,diabinese, chlorpropamide, diabinese, glibenclamide, glibenclamide, glipizide, glipizide, glyburide, glyburide, blimipiride, blimipiride, gliclazide, gliclazide,

glipentide, gliquidone, glipentide, glisolamide,tolazamide, gliquidone, glisolamide, tolazamide, tolbutamide), tolbutamide), a thiazolidinedione a thiazolidinedione (e.g. (e.g.

ciglitazone, darglitazone, ciglitazone, darglitazone, englitazone, englitazone,lobeglitazone, lobeglitazone,MSDC-0602, MSDC-0602, netoglitazone, netoglitazone, pioglitazone, pioglitazone,

rivoglitazone, rosiglitazone, rivoglitazone, rosiglitazone, and andtroglitazone), troglitazone),a aTORC2 TORC2 inhibitor, inhibitor, a urotensin a urotensin II receptor II receptor

agonist, a avasopressin agonist, vasopressinagonist (e.g. agonist DDAVP, (e.g. DDAVP,WAY-141608), or aa VPAC2 WAY-141608), or VPAC2 receptoragonist. receptor agonist. In some

[0447] In some

[0447] embodiments, embodiments, at least at least one of the oneadditional oneoneoforthemore therapeutictherapeutic or more additional agents is agents is an anti-antiobesity an anti-antiobesity agent. agent. InInsome some embodiments, embodiments, the anti-obesity the anti-obesity agent agent is is an apoB-MTP an apoB-MTP

inhibitor (e.g. inhibitor (e.g. dirlotapide, dirlotapide, JTT130, SLX4090, JTT130, SLX4090, usistapide), usistapide), a 3-adrenergic a ß3-adrenergic agonist agonist (e.g. (e.g. amibegron, AZ-40140, amibegron, AZ-40140,CL-316,243, CL-316,243,KRP-204, KRP-204, L-742,791, L-742,791, L-796,568, L-796,568, LY-368,842, LY-368,842, LY- LY 377,604, mirabegron, 377,604, mirabegron, Ro 40-2148, solabegron, Ro 40-2148, solabegron, SWR-0342SA), a bombesin SWR-0342SA), a bombesin receptoragonist, receptor agonist, aa BRS3modulator, BRS3 modulator, a CB1 a CB1 receptor receptor antagonist antagonist or inverse or inverse agonist, agonist, a CCKA aagonist, CCKAagonist, ciliary ciliary factor(CNTF) neurotrophic factor neurotrophic (CNTF) or analog thereof or analog thereof(e.g. axokine, (e.g. NT-501), axokine, ContraveTM NT-501), Contrave

(buproprion/naltrexone),a dopamine (buproprion/naltrexone), a dopamine receptor receptor agonist agonist (e.g. (e.g. bromocriptine), bromocriptine), an 11ß-an 11p

hydroxysteroid dehydrogenase (11p-HSD1) inhibitor, Empatic TM (pramlintide/metreleptin), a 5 Empatic (pramlintide/metreleptin), hydroxysteroid dehydrogenase (11ß-HSD1) inhibitor, a 5-

agonist(e.g. HT2cagonist HT2c (e.g.lorcaserin), lorcaserin),a agalanin galaninantagonist, a ghrelinagonist antagonist,a ghrelin agonist or or antagonist, antagonist, a GLP1 a GLP1

agonist (e.g. agonist (e.g. albiglutide, albiglutide, dulaglutide, exenatide, liraglutide, dulaglutide, exenatide, liraglutide, lixisenatide, lixisenatide, taspoglutide), taspoglutide), aa mixed mixed glucagonreceptor glucagon receptor/ /GLP-1 GLP-1 agonist agonist (e.g. (e.g. MAR-701, MAR-701, ZP2929), ZP2929), an H3 antagonist an H3 antagonist or inverse or inverse agonist, aa human agonist, humanagouti-related agouti-related protein protein (AGRP) (AGRP) inhibitor, inhibitor, leptinleptin or anor an analog analog thereof thereof (e.g. (e.g. metreleptin), aa lipase metreleptin), lipase inhibitor inhibitor (e.g. (e.g. tetrahydrolipstatin), tetrahydrolipstatin), an an MCi MC1 ororMC4agonist (e.g. MC4 agonist (e.g.

afamelanotide, BMS-470539, afamelanotide, bremelanotide,Melanotan BMS-470539, bremelanotide, MelanotanII, II, PF-00446687, PF-00446687,PL-6983, PL-6983, setmelanotide,and setmelanotide, andTHIQ), THIQ), a melanocyte-stimulating a melanocyte-stimulating hormonehormone or analogorthereof, analog athereof, MetAp2 a MetAp2 inhibitor (e.g. inhibitor (e.g. ZGN-433), a monoamine ZGN-433), a monoamine reuptake reuptake inhibitor inhibitor (e.g. buproprion, (e.g. buproprion, sibutramine, sibutramine,

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phentermine,tesofensine), phentermine, tesofensine),a neuromedin a neuromedin U receptor U receptor agonist, agonist, an NPYan NPY antagonist antagonist (e.g. (e.g. 2023206094 18 Jul 2023

velneperit), an velneperit), an opioid opioid receptor receptorantagonist antagonist(e.g. (e.g.naltrexone), naltrexone),ananorexin orexin receptor receptor antagonist antagonist (e.g. (e.g.

almorexant, lemborexant, almorexant, lemborexant, SB-334,867, SB-408,124, SB-649,868, SB-334,867, SB-408,124, SB-649,868,suvorexant), suvorexant), oxyntomodulin oxyntomodulin or an or analogthereof, an analog thereof, PYY PYY or analog or an an analog thereof thereof (e.g.(e.g. PYYi- PYY3-36), PYY1-36, 36 , PYY3-36), QsymiaQsymiaTM

(phentermine/topiramate), an (phentermine/topiramate), anRXR-alpha modulator, aa stearoyl-CoA RXR-alpha modulator, desaturase (SCD-1) stearoyl-CoA desaturase (SCD-1)

inhibitor, or inhibitor, or aa sympathomimetic agent. sympathomimetic agent.

In some

[0448] In some

[0448] embodiments, embodiments, at least at least one oneoneoforthemore of the oneadditional therapeutictherapeutic or more additional agents is agents is a lipid a lipid lowering agent. InInsome lowering agent. some embodiments, embodiments, the lipid the lipid lowering lowering agent agent is is ancoenzyme an acyl acyl coenzyme A A cholesterol acyl cholesterol acyl transferase transferase(ACAT) (ACAT) inhibitor, inhibitor, a bile a bile acid acid reabsorption reabsorption inhibitor, inhibitor, a cholesterol a cholesterol

ester transfer ester transfer protein protein (CETP) inhibitor,a a5-LOX (CETP) inhibitor, 5-LOX inhibitor inhibitor (e.g. (e.g. BAY BAY X 1005), X 1005), a FLAP a FLAP inhibitor inhibitor

(e.g. AM-679), (e.g. AM-679), anan HMG HMG CoA synthase CoA synthase inhibitor, inhibitor, a lipoprotein a lipoprotein synthesis synthesis inhibitor, inhibitor, a low-density a low-density

lipoprotein receptor lipoprotein receptorinducer, inducer,ananLXR LXR receptor receptor modulator, modulator, a microsomal a microsomal triglyceride triglyceride transport transport

inhibitor, niacin, inhibitor, niacin, aa platelet platelet aggregation inhibitor, aa renin-angiotensin aggregation inhibitor, system renin-angiotensin system inhibitor,a squalene inhibitor, a squalene epoxidaseinhibitor, epoxidase inhibitor,aasqualene squalenesynthetase synthetase inhibitor, inhibitor, or or a triglyceridesynthesis a triglyceride synthesis inhibitor. inhibitor.

In some

[0449] In some

[0449] embodiments, embodiments, at least at least one oneoneoforthemore of the oneadditional therapeutictherapeutic or more additional agents is agents is an agent an agentfor for treating treating aa metabolic metabolicdisorder. disorder.In In some some embodiments, embodiments, the for the agent agent for treating treating a a metabolicdisorder metabolic disorderisisananABC ABC transporter transporter activator, activator, ACT-434964 ACT-434964 (Actelion), (Actelion), an ANG-5 an ANG-5 inhibitor, an inhibitor, an angiotensin II antagonist angiotensin II antagonist(e.g. (e.g. MC4262), MC4262), CCX-872, CCX-872, DUR-928 DUR-928 (Durect), (Durect), ESP41091, ESP41091, F-652 (Generon), F-652 (Generon), an an FGF21 agonist (e.g. FGF21 agonist (e.g. BMS-986036), fomepizole(Raptor), BMS-986036), fomepizole (Raptor), an an FXR FXRagonist, agonist, FXR/TGR5 FXR/TGR5 dual dual agonist agonist (e.g. (e.g. INT-767), INT-767), a ghrelin a ghrelin antagonist antagonist (e.g. TZP-301), (e.g. TZP-301), a glucosylceramide a glucosylceramide

synthase inhibitor, synthase inhibitor, a GPR17 a GPR17 modulator, modulator,a aGPR119 agonist, IG-MD-014 GPR119 agonist, (Indigene), IMM-124E IG-MD-014 (Indigene), IMM-124E (Immuron), aa lysosome (Immuron), lysosome pathway pathwaymodulator modulator(e.g. (e.g. CAT5000), CAT5000),a amelanin-concentrating melanin-concentrating hormone hormone receptor 11 antagonist receptor antagonist(e.g. KI-1361-17), (e.g. an MCL1 KI-1361-17), an MCL1inhibitor inhibitor(e.g. CMPX-1023), (e.g. CMPX-1023),ananmTORC1 mTORC1

inhibitor, an inhibitor, an NaCT (e.g.SLC13A5) NaCT (e.g. SLCl3A5) inhibitor, inhibitor, a NHE3 a NHE3 inhibitor inhibitor (e.g. RDX-011, (e.g. RDX-011, tenapanor), tenapanor),

NP003 (Neuraltus), NP003 (Neuraltus), PBI-4050 PBI-4050 (ProMetic), (ProMetic), a proteostasis a proteostasis regulator regulator (e.g. PTI-130, (e.g. PTI-130, PTI-428,PTI-428, PTI- PTI C1811), PS248288 C1811), PS248288(Pharmacopeia/Merck), (Pharmacopeia/Merck),PX-102 PX-102 (Phenex), (Phenex), RG7410. RG7410. RG7652, RG7652, a ROCKa ROCK inhibitor, SBC-104 inhibitor, SBC-104 (Synageva BioPharma), SPX-100 (Synageva BioPharma), SPX-100(Spherix), (Spherix), aa stearoyl stearoyl CoA desaturase CoA desaturase

inhibitor (e.g. inhibitor CVT-12805), (e.g. CVT-12805),TRC150094 (Torrent), or TRC150094 (Torrent), or ZYH7 (ZydusCadila). ZYH7 (Zydus Cadila). In some

[0450] In some

[0450] embodiments, embodiments, at least at least one of the oneadditional oneoneoforthemore therapeutictherapeutic or more additional agents is agents is an agent an agentfor for treating treating steatosis. steatosis. In In some someembodiments, embodiments, the agent the agent for treating for treating steatosis steatosis is anis an adiponectinanalog adiponectin analog(e.g. (e.g.PXPX 811013), 811013), aramchol aramchol (Galmed), (Galmed), an ASK1 an ASKI inhibitor inhibitor (e.g. (e.g. GS-4977, GS-4977, GS-4997),AZD4076 GS-4997), AZD4076 (AstraZeneca), (AstraZeneca), a bilesequestrant a bile acid acid sequestrant (e.g. obeticholic (e.g. obeticholic acid), acid), BL-1060 BL-1060 (Galmed), BMS986171 (Galmed), BMS986171 (Bristol-Myers (Bristol-Myers Squibb), Squibb), a CCR5/CCR2 a CCR5/CCR2 antagonist antagonist (e.g.(e.g. cenicriviroc), cenicriviroc),

cannabidiol, CER-209 cannabidiol, (Cerenis), aa cysteamine CER-209 (Cerenis), cysteamine analog analog (e.g. (e.g.RP-103, RP-103,RP-104), RP-104),DS102 DS102 (DS (DS

Biopharma),EGS21 Biopharma), EGS21 (Enzo), (Enzo), elafibranor elafibranor (Genfit), (Genfit), emricasan emricasan (Idun), (Idun), ethyl eicosapentaenoic ethyl eicosapentaenoic acid acid

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(Mochida), an (Mochida), an FXR agonist, aa GPBAR1 FXR agonist, agonist(e.g. GPBAR1 agonist (e.g. RDX009), RDX009),GR-MD-02 GR-MD-02 (Galectin (Galectin 2023206094 18 Jul 2023

Therapeutics),leucine/sildenafil/metformin Therapeutics), leucine/sildenafil/metformin (NuSirt), (NuSirt), LCQ908 LCQ908 (Novartis), (Novartis), LJN452 (Novartis), LJN452 (Novartis), a a LOXL2 LOXL2 inhibitor (e.g. inhibitor (e.g. simtuzumab), simtuzumab), MAT-8800 (Matinas),MB-10866 MAT-8800 (Matinas), MB-10866 (Metabasis), (Metabasis), an an miR miR-

103/107 inhibitor 103/107 inhibitor (e.g. RG-125), (e.g. MK-4074 RG-125), MK-4074 (Merck (Merck &&Co.), Co.), nalmefene nalmefene (TaiwanJ), (TaiwanJ), nivocasan nivocasan (Gilead), NGM-282 (Gilead), (NGM NGM-282 (NGM Biopharmaceuticals), Biopharmaceuticals), an an omega-3 omega-3 carboxylic carboxylic acidacid or or mixture mixture ofof the the

same (e.g. (e.g. Epanova M same Epanova TPX-102 ), PX-102 (Phenex), (Phenex), PX-104 PX-104 (Phenex), (Phenex), remogliflozin remogliflozin etabonate etabonate (Kissei), (Kissei),

saroglitazar (Zydus-Cadila), saroglitazar (Zydus-Cadila),SAR-548304 SAR-548304 (sanofi-aventis), (sanofi-aventis), tipelukast tipelukast (Kyorin), (Kyorin), ursodeoxycholic ursodeoxycholic

acid, VK2809 acid, (Viking), VK2809 (Viking), or XL335 or XL335 (Exelixis). (Exelixis).

[0451] In some

[0451] In some embodiments, embodiments, at least at least one of the oneadditional oneoneoforthemore therapeutictherapeutic or more additional agents is agents is an agent an agentfor for treating treating inflammation. inflammation.In In some some embodiments, embodiments, thefor the agent agent for treating treating inflammation inflammation

reducesthe reduces thedifferentiation differentiation ororactivation activationofofTh17 Th7 cells.InInsome cells. some embodiments, embodiments, the agent the agent for for treating inflammation treating inflammation is isa acaspase caspase inhibitor inhibitor (e.g.emricasan), (e.g. emricasan), a TGF-P a TGF-ß inhibitor, inhibitor, an IL-IP an IL-1ß

inhibitor, an inhibitor, an IL-6 inhibitor, an IL-17 IL-6 inhibitor, IL-17inhibitor, inhibitor, an an IL-17a IL-17ainhibitor, inhibitor,ananIL-17F IL-17F inhibitor, inhibitor, an an IL-21 IL-21

inhibitor, an inhibitor, an IL-23 inhibitor (e.g. IL-23 inhibitor (e.g. guselkumab), guselkumab),IMM-124E, IMM-124E, a RORyt a RORyt inhibitor inhibitor (e.g. JTE-151) (e.g. JTE-151) a a RORa ROR inhibitor, inhibitor, solithromycin solithromycin (Cempra), (Cempra), or a vascular or a vascular adhesion adhesion protein-1protein-i inhibitorinhibitor (e.g. (e.g. PXS- PXS 4728A). 4728A).

[0452]

[0452] In some some embodiments, In embodiments, at least at least one of the oneadditional oneoneoforthemore therapeutictherapeutic or more additional agents is agents is an agent an agentfor fortreating treating fibrosis. fibrosis. In In some someembodiments, embodiments, the agent the agent for treating for treating fibrosis fibrosis is is cenicriviroc (Tobira/Takeda), cenicriviroc (Tobira/Takeda), CNX-014/023/024/025 CNX-014/023/024/025 (Connexios), (Connexios), an endothelin an endothelin antagonist antagonist (e.g. A192621, (e.g. ambrisentan, A192621, ambrisentan, atracentan, atracentan, bosentan, bosentan, BQ-123, BQ-123, BQ-788,BQ-788, macitentan, macitentan, sitaxentan, sitaxentan,

tezosentan, zibotentan), tezosentan, zibotentan),etanercept, etanercept,evitar evitar(AdeTherapeutics), (AdeTherapeutics), a fibroblast a fibroblast growth growth factor factor

inhibitor, aa galectin-3 inhibitor, galectin-3 inhibitor, inhibitor, imatinib, imatinib, IVA337 (Inventiva), IVA337 (Inventiva), N-acetylcysteine, N-acetylcysteine, nintedanib, nintedanib, pirfenidone, pirfenidone, RG6069 (Roche), SP20102 RG6069 (Roche), SP20102(Sarfez), (Sarfez), tipelukast tipelukast (Kyorin), (Kyorin),oror XOMA 089(Xoma). XOMA 089 (Xoma).

[0453] some embodiments, In embodiments,

[0453] In some the non-alcoholic fatty liverfatty the non-alcoholic liverisdisease disease is steatosis. steatosis. In some In some embodiments, embodiments, thethe non-alcoholic non-alcoholic fattyfatty liver liver disease disease is non-alcoholic is non-alcoholic steatohepatitis steatohepatitis (NASH). (NASH). In In someembodiments, some embodiments, the non-alcoholic the non-alcoholic fatty fatty liver liver disease disease is liver is liver fibrosis fibrosis caused caused by NASH. by NASH. In In someembodiments, some embodiments, the non-alcoholic the non-alcoholic fatty fatty liver liver disease disease is liver is liver cirrhosis cirrhosis caused caused by NASH. by NASH. In In someembodiments, some embodiments, the non-alcoholic the non-alcoholic fatty fatty liver liver disease disease is hepatocellular is hepatocellular carcinoma carcinoma (HCC) (HCC) caused by caused by NASH. NASH.

[0454] Those

[0454] Those additional additional agents agents maymay be be administered administered separatelyfrom separately from a a providedcompound provided compound or composition or thereof,asaspart composition thereof, partofofa amultiple multiple dosage dosage regimen. regimen. Alternatively, Alternatively, those those agentsagents may be may be part part of of a a single single dosage form,mixed dosage form, mixed together together withwith a provided a provided compound compound in a composition. in a single single composition. If administered If aspart administered as partofofaa multiple multipledosage dosage regime, regime, the the two two active active agents agents may may be be submitted submitted

simultaneously,sequentially simultaneously, sequentially or or within within a period a period of time of time fromfrom one another, one another, normally normally within within five five hoursfrom hours fromoneone another. another.

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[0455] As used

[0455] As used thethe herein, herein, term term "combination,""combined," "combination," related conjunction"andandrelated "combined,""in"inconjunction" 2023206094 18 Jul 2023

terms refers terms refers to to the the simultaneous simultaneousor orsequential sequential administration administration of therapeutic of therapeutic agents agents in accordance in accordance

with this with this invention. invention. For Forexample, example, a provided a provided compound compound may be administered may be administered with with another another therapeutic agent therapeutic agentsimultaneously simultaneously or sequentially or sequentially in separate in separate unitunit dosage dosage formsforms or together or together in a in a single unit single unit dosage dosageform. form.Accordingly, Accordingly, the present the present invention invention provides provides a single a single unit dosage unit dosage form form comprisinga aprovided comprising provided compound, compound, an additional an additional therapeutic therapeutic agent, agent, and a pharmaceutically and a pharmaceutically

acceptablecarrier, acceptable carrier, adjuvant, adjuvant,ororvehicle. vehicle.

[0456] The The

[0456] amount amount of both, of both, a provided a provided compound compound and additional and additional therapeutic therapeutic agent agent (in(inthose those compositionswhich compositions which comprise comprise an additional an additional therapeutic therapeutic agent agent as as described described above) above) that may that be may be combinedwith combined with thethe carrier carrier materials materials to to produce produce a single a single dosage dosage formvary form will willdepending vary depending upon upon the host the treated and host treated and the theparticular particular mode modeof of administration. administration. Preferably, Preferably, compositions compositions of thisof this invention should invention should be be formulated formulated so sothat a dosage that of of a dosage between 0.01 between - 100 0.01 100mg/kg mg/kg body body weight/day weight/day

of aa provided of compound provided compound canadministered. can be be administered. In those

[0457] In those

[0457] compositions compositions which comprise which comprise an additional agent, that agent, therapeutictherapeutic an additional that additional additional therapeutic agent therapeutic agentand anda aprovided provided compound compound may may act act synergistically. synergistically. Therefore, Therefore, theofamount the amount of additional therapeutic additional therapeuticagent agentininsuch suchcompositions compositions willwill be less be less thanthan thatthat required required in a in a monotherapy monotherapy utilizing utilizing only only that that therapeutic therapeutic agent. agent. In such In such compositions compositions a dosage a dosage of of between between 0.01 -- 100 0.01 100 µg/kg jg/kgbody body weight/day weight/day of additional of the the additional therapeutic therapeutic agent agent can becan be administered. administered.

[0458] The The

[0458] amount amount of additional of additional therapeuticagent therapeutic agentpresent presentinin aa composition composition comprising comprising aa providedcompound provided compoundwill will be nobemore no more than than the the amount amount thatnormally that would would be normally be administered administered in a in a compositioncomprising composition comprising thatthat therapeutic therapeutic agent agent as only as the the only active active agent. agent. Preferably Preferably the the amount amount of additional of therapeutic agent additional therapeutic agentinina aprovided providedcomposition composition will will rangerange from from about about 50% to 50% 100% to of 100% of the amount the amountnormally normally present present in aincomposition a composition comprising comprising that asagent that agent as thetherapeutically the only only therapeutically active agent. active agent. EXEMPLIFICATION EXEMPLIFICATION

[0459] As depicted

[0459] As depicted in the in the Examples Examples below, in in below, certainexemplary certain embodiments, exemplaryembodiments, compounds compounds

and solid and solid forms formsare areprepared prepared according according to the to the preceding preceding general general procedures. procedures. It will Itbewill be appreciatedthat, appreciated that, although althoughthethegeneral generalmethods methods depict depict the the synthesis synthesis of certain of certain compounds compounds of the of the present invention, present invention, the thefollowing followingmethods, methods, and and other other methods methods known known to to ordinary one of one of ordinary skill in skill in the art, the art, can can be be applied to all applied to all compounds compounds andand subclasses subclasses and species and species of each of each of these of these compounds, compounds,

as described as herein. described herein.

Experimentalprocedures: Experimental procedures: As used

[0460] As used

[0460] herein, "V""V"= herein, volumes, = volumes, "v/w"= "v/w" volume/weight = volume/weight ratio, ratio, "v/v"= "v/v" =

volume/volume volume/volume ratio, ratio, andand "w/w"= "w/w" weight/weight = weight/weight ratio. ratio.

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Example 1. Example 1. Production Production of ofAmorphous Amorphous Compound Compound 1 1 2023206094 18 Jul 2023

1 gram

[0461] 1 gram

[0461] of Compound of Compound 1, prepared 1, prepared according according to the to the method method described described in in US US 2013/0123231A1, 2013/0123231 Al,was wascompletely completelydissolved dissolvedinin 10 10 mL mLdichloromethane. dichloromethane. The The dichloromethane dichloromethane

solution was solution wasevaporated evaporated rapidly rapidly under under vacuum vacuum at 40resulting at 40 °C, °C, resulting in amorphous in amorphous Compound Compound 1 1 havingthe having theXRPD XRPD pattern pattern depicted depicted in Figure in Figure 18. 18. Example2.2.Production Example Productionof of Form Form I of I of Compound Compound 1 1

50 milligrams

[0462] 50 milligrams

[0462] of amorphous of amorphous Compound Compound 1, prepared 1, prepared according according to the the method to method of of Example Example 1, 1, waswas slurried slurried in in acetone acetone and and subjected subjected to temperature to temperature cycling cycling from 40from °C to40 25°C °C,toin 25 °C, in 4 hh cycles 4 cycles for for 72 72 h. h. Solid SolidForm Form I of I of Compound Compound 1 was 1collected was collected by filtration. by filtration. Form I Form was I was determined to be determined be an an neat neatpolymorph polymorph of of Compound Compound 1.1. Form FormI Iwas wasdetermined determinedtotohave havepoor poor aqueoussolubility aqueous solubilityatatpHpH 5.5andand 5.5 below below (< µg/mL), (< 10 10 ig/mL), with awith logD avalue logDofvalue 1.06 of at 1.06 at pH pH 7.4. 7.4. DSC DSC

[0463] The The

[0463] curvecurve of Form I of ICompound of Form of Compound 1 (Figure 3A and3A 1 (Figure and Figure Figure 3B) indicates 3B) indicates an an endothermictransition endothermic transitionwith with onset onset at at about about 189-193 189-193 °C attributed °C attributed to a melt. to a melt. Thecurve The TGA TGAofcurve of FormI IofofCompound Form Compound 1 shows 1 shows no significant no significant weight weight loss up loss up at150 at about about 150 °C, indicating °C, indicating an an unsolvatedphase. unsolvated phase.TheThe moisture moisture sorption sorption curvecurve of Form of Form I of Compound I of Compound 1 also indicates 1 also indicates that that FormI Iisis slightly Form slightly hygroscopic hygroscopicshowing showing around around a 0.45% a 0.45% weight weight gain at gain aboutat95% about 95% RH. An RH. An XRPD XRPD analysis analysis of the of the sample sample afterafter the the DVS DVS experiment experiment shows shows that that the material the material had not had not changed changed forms. forms.

[0464] SingleSingle

[0464] crystals crystals of Form were obtained were Iobtained of IForm from an attempted from an attempted salt formation formation experiment. salt experiment. 0.5 mL 0.5 Methylethyl mL Methyl ethyl ketone ketone (MEK) wasadded (MEK) was addedtoto40.5 40.5milligrams milligrams Compound Compound 1 to 1 to form form a a suspension.InIna aseparate suspension. separatevial, vial, 10.2 10.2milligrams milligramsof of L-proline L-proline was was dissolved dissolved in mL in 0.1 0.1H2O mL H20 and and the solution the solution was wasadded addedto to theCompound the Compound 1 suspension. 1 suspension. The was The sample sample was at slurried slurried at °C about 60 about 60 °C for about for about 55 days daysand andformed formed a golden a golden yellow yellow solution. solution. The solution The solution wascooled was crash crash to cooled about to about

2-8 °C 2-8 °Cand andremained remained at about at about 2-8 2-8 °C about °C for for about 4 producing 4 days days producing a goldena yellow goldensolution yellow with solution with

white oil. white oil. The samplewaswas The sample placed placed at room at room temperature temperature and about and after after 14 about 14solids days, days, were solids were observedininsolution. observed solution.

[0465] A suitable

[0465] A suitable singlesingle crystal crystal was selected was selected and analyzed and analyzed by single-crystal by single-crystal X-ray X-ray diffractometry. AAcolorless diffractometry. colorlessplate platehaving having approximate approximate dimensions dimensions of 0.19of X 0.19 0.13 Xx 0.06 0.13 mm³, x 0.06 mm3 ,

wasmounted was mounted onnylon on a a nylon looploop in random in random orientation. orientation. Preliminary Preliminary examination examination and data and data collection were collection wereperformed performed onRigaku on a a Rigaku SuperNova SuperNova diffractometer, diffractometer, equipped equipped with with a copper a copper anode microfocus anode microfocus sealed sealed X-ray X-ray tube tube (Cu K ak==1.54184 (Cu Ka 1.54184A) anda aDectris Å) and Dectris Pilatus3 Pilatus3 RR 200K 200K

hybrid pixel hybrid pixelarray arraydetector. detector. Cell Cellconstants constantsandand an an orientation orientation matrix matrix for for datadata collection collection werewere

obtainedfrom obtained fromleast-squares least-squares refinement refinement using using the setting the setting angles angles of 15725 of 15725 reflections reflections in theinrange the range 3.5010° < 3.5010° <A 0<< 77.2150°. 77.2150°. The The space space group group was was determined determinedby bythe the program programCRYSALISPRO CRYSALISPROto be to be

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C2221 (internationaltables C2221 (international tablesno.no.20). 20).TheThe data data were were collected collected to ato a maximum maximum diffraction diffraction angle (20) angle (2) 2023206094 18 Jul 2023

of 155.284° of 155.284°atatroom room temperature. temperature.

[0466] It wasIt found

[0466] was found thatcrystal that the the crystal systemsystem of Formof I Form I is orthorhombic is orthorhombic and group and the space the space is group is C2221.The C2221. The cellparameters cell parameters and and calculated calculated volume volume are: a are: a = 14.77743(18)A, = 14.77743(18) b = 14.62619(16) Å, b = 14.62619(16)

A, Å, cc = 51.7778(8)Å,A,a =a 90°, = 51.7778(8) = 90°, ß =§= 90°,= y90°, 90°, = 90°, V= 11191.1(3) V = 11191.1(3) A3. Å3. The The molecular molecular weight isweight is

569.62g gmol¹ 1 with mol-with Z =Z= 16, 16, resulting in aincalculated a calculated density of 1.352 3 . Standard 569.62 resulting density of 1.352 gcm- g cm³. Standard

uncertainty for uncertainty for this this data data is is written written in in crystallographic parenthesisnotation, crystallographic parenthesis notation,e.g. e.g.0.123(4) 0.123(4)is is equivalent toto 0.123 equivalent 0.123± ±0.004. The 0.004. The quality quality of of thethe structure structure obtained obtained is high, is high, as indicated as indicated by fit by the the fit residual, R, residual, R, of of 0.0446 (4.46%).R-factors 0.0446 (4.46%). R-factors in in thethe range range 2-6% 2-6% are quoted are quoted to be to thebe the reliably most most reliably determinedstructures. determined structures.

[0467] It is

[0467] thatForm contemplatedthat It iscontemplated form of stableform the most stable FormI Iisis the ofCompound 1. Compound 1.

Example3.3.Production Example Productionof of Form Form II II of of Compound Compound 1 1

[0468] 100 100

[0468] milligrams milligrams of amorphous of amorphous Compound Compound 1, prepared 1, prepared according according to the the method to method of of Example Example 1, 1, waswas slurried slurried in in dimethylformamide dimethylformamide (DMF) (DMF) and and subjected subjected to temperature to temperature cycling cycling from4040°C°Ctoto2525°C,°C,in in4 h4 hcycles from cycles forfor 72 72 h. h. Solid Solid Form Form II Compound II of of Compound 1 was collected 1 was collected by by filtration. The filtration. TheDSC curve shows DSC curve the first shows the firstendotherm endothermaround around74 74 °C °C and and aa second second endotherm endotherm

was observed was observed above above 180 180°C°C(Figure (Figure 37). 37). Example4.4.Production Example Productionof of Form Form IIIIII of of Compound Compound 1 1

[0469] 100 100

[0469] milligrams milligrams of amorphous of amorphous Compound Compound 1, prepared 1, prepared according according to the the method to method of of Example Example 1, 1, waswas slurried slurried in in dimethylsulfoxide dimethylsulfoxide (DMSO) (DMSO) and subjected and subjected to temperature to temperature cycling cycling from4040°C°Ctoto2525°C,°C,in in4 h4 hcycles from cycles forfor 72 72 h. h. Solid Solid Form Form IIICompound III of of Compound 1 was collected 1 was collected by by filtration. Thermogravimetric filtration. analysis Thermogravimetric analysis of Form of Form III showed III showed a steady a large large steady weight weight loss, loss, suggesting that suggesting thatForm Form III IIImay maybe bea aDMSO solvate of DMSO solvate of Compound Compound 1.1.NoNo additionalthermal additional thermalevents events wereobserved were observed above above the the solvent solvent lossloss (Figure (Figure 38). 38).

Example5.5.Production Example Productionof of Form Form IV Compound IV of of Compound 1 1

[0470] 500 500

[0470] milligrams milligrams of amorphous of amorphous Compound Compound 1, prepared 1, prepared according according to the the method to method of of Example Example 1, 1, waswas slurried slurried in in methanol methanol and subjected and subjected to temperature to temperature cyclingcycling from 40 from °C to 40 25 °C °C, to 25 °C, in 44 hh cycles in for 48 cycles for hours. Solid 48 hours. SolidForm FormIV IV of Compound of Compound 1 was 1 was collected collected by filtration. by filtration. DSC DSC curve curve of Form of Form IVIV comprises comprises an endothermic an endothermic transition transition with at with onset onset at 85 85 °C, °C, 190 about about °C, 190 °C, and and about about 202 °C 202 °C and and exotherm exothermat at 146 146 °C. °C. Thermogravimetric

[0471] Thermogravimetric

[0471] analysis analysis indicated indicated a weight a weight loss 4.2%oror4.7% lossofof4.2% and 4.7%and correspondingendotherm corresponding endotherm between between 82-92 82-92 °C, indicating °C, indicating that that Form IV Form IV is a methanol is a methanol solvate of solvate of Compound Compound 1. 1.Upon Upon furtherheating further heatingthe thesample sampletoto 120 120 °C, °C, XRPD XRPD analysisconfirmed analysis confirmedthat that the the samplehad sample hadconverted converted to Form to Form I. I.

Example 6. Example 6. Production Production of ofForm Form VV of ofCompound Compound 11

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[0472] 100 100

[0472] milligrams milligrams of amorphous of amorphous Compound Compound 1, prepared 1, prepared according according to the the method to method of of 2023206094 18 Jul 2023

Example1, 1,waswas Example slurried slurried in in N-methyl-2-pyrrolidone N-methyl-2-pyrrolidone (NMP) (NMP) and and subjected subjected to temperature to temperature cycling cycling from4040°C°Ctoto2525°C,°C,in in4 h4 hcycles from cycles forfor 72 72 h. h. Solid Solid Form Form V of V of Compound Compound 1 was collected 1 was collected by by filtration. Thermogravimetric filtration. analysis Thermogravimetric analysis of Form of Form V showed V showed a large asteady large weight steady loss weight loss of of 13.5%, 13.5%, suggesting that suggesting thatForm Form V V may be aa NMP may be solvateofofCompound NMP solvate Compound 1. 1. No No additionalthermal additional thermalevents events wereobserved were observed above above the the solvent solvent lossloss (Figure (Figure 39). 39).

Example7.7.Production Example Productionof of Form Form VI Compound VI of of Compound 1 1

[0473] 100 100

[0473] milligrams milligrams of amorphous of amorphous Compound Compound 1, prepared 1, prepared according according to the the method to method of of Example Example 1, 1, waswas dissolved dissolved in toluene in toluene and either and either crashcrash cooled cooled at -18at°C-18 or °C the or the toluene toluene was was evaporated. InInboth evaporated. both cases,solid cases, solidForm Form VICompound VI of of Compound 1 was collected 1 was collected by filtration. by filtration. XRPD XRPD analysis indicated analysis indicatedaadistinct distinct toluene toluenesolvate solvateform formof of Compound Compound 1. 1. Example8.8.Production Example Productionof of Form Form VIIV1 of Compound of Compound 1 1

[0474] 100 100

[0474] milligrams milligrams of Form of Form IVCompound IV of of Compound 1, prepared 1, prepared according according to the the method to method of of Example Example 5, 5, was was heated heated to °C to 80 80 in°Caninoven. an oven. Form Form VII wasVII was confirmed confirmed to be a desolvated to be a desolvated form of form of FormIV, Form IV, produced produced by by drying drying the the methanol solvate Form methanol solvate IV. XRPD Form IV. XRPD analysisshowed analysis showed thatwhile that while FormVII Form VIIhadhad a similar a similar diffraction diffraction pattern pattern to to that that of of Form Form I, there I, there were were a number a number of distinct of distinct

peaksbetween peaks betweenthethe twotwo forms forms which which confirmed confirmed them to them to be distinct be distinct crystal crystal forms. Differential forms. Differential

scanningcalorimetry scanning calorimetry (DSC) (DSC) results results (Figure (Figure 40) were 40) were consistent consistent with thermogravimetric with thermogravimetric analysis. analysis.

Onsetofofthe Onset thefirst first endothermic event endothermic event waswas observed observed at 133.7 at 133.7 °C (peak °C (peak at °C), at 141.4 141.4with °C),the with the peak peak of the of the exotherm exotherm atat151.6 151.6°C.°C.TheThe main, main, sharpsharp endotherm endotherm was observed was observed withatan with an onset onset at 192.3 °C 192.3 °C(peak (peakatat195.0 195.0°C). °C).A smaller A smaller endotherm endotherm with a with peak aatpeak 207.0at°C 207.0 °C wastolikely was likely to indicate indicate formationofofa ahigher formation highermelting melting crystallineform. crystalline form. Dynamic Dynamic vapor vapor sorption sorption (DVS) of (DVS) analysis analysis Form of Form VII indicated VII indicatedthe thematerial materialwas was moderately moderately hygroscopic hygroscopic (>4%uptake (>4% water wateratuptake at 90% 90% RH), RH), and post and post DVSanalysis DVS analysis showed showednonochange changeininform. form. The Theuptake uptakebetween between4040and and70% 70% RH RH could could potentially potentially

be indicative be indicative of ofhydrate hydrateformation formation (tentatively (tentatively assigned assigned the the namename Form Form IX). Karl-Fischer IX). Karl-Fischer

analysis showed analysis showeda water a water content content of 0.503%, of 0.503%, consistent consistent with observations with observations of ambient of ambient humidity humidity

measuredduring measured during DVSDVS analysis. analysis. NMR NMR and and confirmed IR data IR data confirmed the integrity the structural structural ofintegrity of Compound Compound 1 present. Aqueous 1 present. Aqueous solubilityofof Form solubility FormVII VIIwas wasdetermined determinedtotobe be 0.109 0.109 mg/mL. mg/mL. XRPD XRPD analysis analysis confirmed confirmed that that prolonged prolonged exposure exposure to watertoresulted water resulted in the conversion in the conversion of Form of Form VII to VII to Form FormI.I. However, However, FormForm VIIdetermined VII was was determined to be chemically to be chemically and physically and physically stable stable following7 7days following daysofofstorage storageat at4040°C°C andand 75% 75% RH. RH. No No in change change in form form was was and observed, observed, the and the purity was purity wasdetermined determinedto to be be 99.85%. 99.85%.

Example9.9.Production Example Productionof of Form Form VIII VIII of Compound of Compound 1 1

[0475] 100 100

[0475] milligrams milligrams of anhydrous of anhydrous VII VII FormForm of Compound was heated 1 was 1heated of Compound to °C. to 195 195 °C. Consistentwith Consistent withthe theDSC DSC analysis analysis of Form of Form VII, analysis VII, XRPD XRPD analysis of the resulting of the resulting solidthat solid showed showed that

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FormVIII Form VIII of of Compound Compound1 was 1 was produced.TheThe produced. NMRNMR spectrum spectrum was found was found to be to be consistent consistent withwith 2023206094 18 Jul 2023

that of that of Compound 1, and Compound 1, and HPLCHPLC analysis analysis of FormofVIII Form VIII indicated indicated a purity aofpurity 99.4%.of 99.4%. Form VIII Form VIII wasalso was alsoprepared preparedbyby running running 50 grams 50 grams of anhydrous of anhydrous Form I Form I of Compound of Compound 1 through a 1Leistriz through a Leistriz twin screw twin screwextruder extruderutilizing utilizingmultiple multiple heat heat zones zones of about of about 170about 170 to to about 193 °C193 and°C and a a screw screw speed ofof3030rpms. speed rpms.

[0476] DSC DSC

[0476] analysis analysis of Form of Form VIII VIII showed showed the same the same sharpsharp peakpeak withwith onset onset at 204.7 at 204.7 °C °C (peak (peak

at 208.1 at C), corresponding 208.1 °C), correspondingto to thethe melting melting point point of Form of Form VIII.VIII. Further Further DSC analysis DSC analysis of Form Iof Form I indicate that indicate that cooling cooling aa melted meltedsample sampleof of Form Form I, followed I, followed by a by a second second heating heating event resulted event resulted in in an endotherm an endotherm with with onset onset at 204.7 at 204.7 °C (peak °C (peak at 208.1 at 208.1 C), indicating °C), indicating that VIII that Form FormisVIII is directly directly

producedfrom produced from Form Form I upon I upon heating heating in manner. in that that manner.

[0477] DSC DSC

[0477] The The shownshown curvecurve in Figure in Figure 16 shows 16 shows that Form VIII VIII that Form comprises comprises an endotherm an endotherm

with onset with onsetatat about about205 205°C.°C. Example10. Example 10.Competitive Competitive Slurrying Slurrying of of Form Form I and I and FormForm VII VII

[0478] Competitive

[0478] Competitive slurrying slurrying of of Form Form I and I and Form Form VIIVII in in acetone,acetonitrile:water acetone, acetonitrile:water (10%), (10%),

ethanol, and ethanol, andethyl ethylacetate, acetate, at at both bothambient ambienttemperature temperature and and 60 resulted 60 °C, °C, resulted in conversion in conversion to to FormI, Form I, as as confirmed confirmed by by XRPD andDSC. XRPD and DSC. Example11. Example 11.Competitive Competitive Slurrying Slurrying of of Form Form I and I and FormForm VIII VIII

[0479] Competitive

[0479] Competitive slurrying slurrying of Form of Form I and I and Form VIIIForm VIII inacetonitrile:water in acetone, acetone, acetonitrile:water (10%), (10%), ethanol, and ethanol, andethyl ethylacetate, acetate, at at both bothambient ambienttemperature temperature and and 60 resulted 60 °C, °C, resulted in conversion in conversion to to FormI, Form I, as as confirmed confirmed by by XRPD andDSC. XRPD and DSC. Example12. Example 12.Competitive Competitive Slurrying Slurrying of of Form Form I and I and FormForm VIII VIII Competitive

[0480] Competitive

[0480] of Form of slurrying slurrying Form I and I and Form VIIIForm in a 1:1 in a in VIIIratio 1:1a ratio in aof solution solution 6:4 of 6:4 ethanol:wateratatroom ethanol:water room temperature temperature for for about about two weeks two weeks resulted resulted in conversion in conversion to Form to Form I as I as confirmed by confirmed by XRPD. XRPD.

[0481] of theof The results

[0481] The results the competitive competitive slurrying analysisanalysis slurrying indicated indicated that that Form Form I is I is the the more more thermodynamically thermodynamically stable stable formform between between 22-60 22-60 °C. °C.VIIIForm Form couldVIII could be potentially be potentially the more the more stable form stable formatat high hightemperatures. temperatures. Example 13. Example 13. Production Production of ofCompound Compound 11 Sodium Sodium Form FormII Sodium

[0482] Sodium

[0482] Form Form I (hydrate) was was I (hydrate) prepared prepared as follows. as follows. 3.48 3.48 g ofanhydrous g of anhydrous Form Form I of I of

Compound Compound 1 was 1 was placedinina abeaker placed beaker with with 0.27 0.27 gg of of NaOH and4040mLmL NaOH and of of water. The water. Thesample sample was was

heated and heated andstirred stirred until until solution solution became became clear.Next, clear. Next, the the solution solution was was filtered filtered into into a vial a vial and and placedinin aa vacuum placed vacuum centrifuge. centrifuge. The The resulting resulting solids solids were were slurried slurried in ethyl in ethyl acetate acetate and and then then washed with washed with acetone, acetone, filtered, filtered, andand dried. TheThe dried. XRPD XRPD pattern patternofofCompound Compound 11 Sodium SodiumForm FormI Iisis shownininFigure shown Figure19.19.TheThe DSC DSC curve curve is shown is shown in 20 in Figure Figure 20 and indicates and indicates multiple endothermic multiple endothermic

transitions with transitions onsetatat 37 with onset 37 °C °Cand and283283 °C.°C. The The TGA is TGA curve curve is in shown shown Figurein21 Figure 21 and adisplays and displays a

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weightloss weight (4.1%RT RT loss(4.1% to 175 to 175 °C) °C) that that was was identified identified as water as water based based on TGA-Mass on TGA-Mass Spectrometry Spectrometry

(TGA-MS).Weight Weight loss above 250250 °C °C is is attributed to to decomposition. The dynamic dynamicvapor vapor 18 Jul 2023

(TGA-MS). loss above attributed decomposition. The

sorption curve sorption curveindicates indicatesthat thatthe theform formabsorbs absorbs about about 32 weight 32 weight % of % of water water up to up to 95% RH 95% RH (relative humidity) (relative at 25 humidity) at 25 °C. °C.TheThe material material was was found found to have to have deliquesced deliquesced post experiment. post experiment.

Example 14. Example 14. Production Production of ofCompound Compound 11 Sodium Sodium Form FormII 1

[0483] Compound

[0483] Compound 1 Sodium 1 Sodium Form IIForm II (variable (variable hydrate) hydrate) was prepared was prepared as follows. as follows. 4.0 4.0 g g of of anhydrous Form anhydrous FormI I of of Compound Compound 1 was 1 was placedinina abeaker placed beaker with with 0.4 0.4 gg of of NaOH andabout NaOH and about4040mL mL 2023206094

of water. of Thesample water. The sample waswas heated heated and stirred and stirred untiluntil solution solution became became clear. clear. Next, Next, the the solution solution was was filtered into filtered into aavial vialand and placed in aa vacuum placed in centrifuge.TheThe vacuum centrifuge. resulting resulting solids solids from from vacuumvacuum

centrifuge were centrifuge werewashed washedwithwith 10% water 10% water in acetonitrile, in acetonitrile, and the and then thensolids the solids were and were dried dried and then then slurried in slurried in ethyl ethyl acetate. Thesample acetate. The sample were were sonicated sonicated for about for about 1 hour 1 hour and left and then thentoleft sittoat sitroom at room temperature.TheThe temperature. solids solids were were slurried slurried in acetone in acetone and aand a portion portion was filtered was filtered to yield to yield solids. solids. The The XRPDpattern XRPD patternofofCompound Compound 1 Sodium 1 Sodium Form Form II isII shown is shown in Figure in Figure 22.22. The The DSCDSC curve curve is shown is shown

in Figure in 23and Figure 23 andindicates indicatesmultiple multiple endothermic endothermic transitions transitions with with onsetonset at about at about 19, about 19, about 78 and78 and about 136 about 136 °C. °C. The The TGA TGAcurve curveisisshown shownininFigure Figure 24 24and and displays displays aa weight weight loss loss(about (about24% 24% RT RT

to about to about 150 150°C) °C)indicating indicatinga solvate a solvate thatwaswas that identified identified as as water water based based on TGA-MS. on TGA-MS. A second A second sample of sample of Compound 1 Sodium Compound 1 Sodium Form Form II was II was prepared prepared when when 10921092 mgForm mg of of Form I of ICompound of Compound 1 1 wasplaced was placedinina avial vialwith with7676mgmg of of NaOH NaOH and 10and 10 water. mL of mL ofSample water. sonicated Sample but sonicated but solids solids till till persisted. Another persisted. Another 45mg of NaOH 45mg of NaOH asasadded addedwith withananadditional additional 10 10 mL mLand andthe the solution solution became became

clear. Sample clear. Samplewaswas then then centrifuge centrifuge evaporated evaporated overweekend over the the weekend to yieldtodry yield dry solids. solids. These These solids solids werethen were thenslurried slurriedininEtOAc EtOAcfor for approximately approximately 10 days. 10 days. The resulting The resulting solids solids had the had samethe same XRPDpattern XRPD patternasas Compound Compound 1 Sodium 1 Sodium Form Form II and II and waswas found found to only to only have have about about 10.4% 10.4% weight weight

loss up loss to about up to about 175 175°C. °C.This This maymay indicate indicate that that thisthis formform can have can have anywhere anywhere from from about about 4-10 4-10 molesofofwater. moles water.Weight Weight lossloss above above aboutabout 250 250 °C is °C is attributed attributed to decomposition. to decomposition. The The dynamic dynamic vaporsorption vapor sorptioncurve curveindicates indicatesthat thatthetheform form absorbs absorbs about about 35 weight 35 weight % ofup % of water water up to to about about 95%RHRH 95% at about at about 25 °C. 25 °C. The material The material was tofound was found have to have deliquesced deliquesced post experiment. post experiment.

Example 15. Example 15. Production Production of ofCompound Compound 11 Calcium Calcium Form FormII Compound

[0484] Compound

[0484] Form IForm 1 Calcium 1 Calcium I (hydrate) (hydrate) was prepared was prepared as follows. as follows. g ofg anhydrous 4.47 4.47 of anhydrous FormII of Form of Compound Compound 1 1 wasplaced was placedininaa beaker beaker with with 0.4 0.4 gg of ofKOH and about KOH and about 25 25 mL mLofofwater. water. Thesample The samplewaswas heated heated and and stirred stirred until until solution solution became became clear.clear. Next, Next, 0.5calcium 0.5 g of g of calcium chloridechloride

wasadded was addedandand thethe sample sample was was cooled cooled to temperature to room room temperature and left and left for to stir to stir forhours. a few a few The hours. The samplewas sample wasthen then filteredandand filtered slurried slurried in in about about 20%20% waterwater in acetonitrile in acetonitrile to yield to yield a hazy a hazy solution. solution.

Thesample The samplewaswas sonicated sonicated for for about about one hour one hour to yield to yield a slurry. a slurry. The sample The sample was was then then filtered filtered and and dried in dried in aa nitrogen boxatat 55 psi. nitrogen box psi. The TheXRPD XRPD pattern pattern of Compound of Compound 1 Form 1 Calcium Calcium Form in I is shown I is shown in Figure 25. Figure 25. The The DSCDSC curvecurve is shown is shown in Figure in Figure 26 and 26 and indicates indicates multiplemultiple endothermic endothermic transitionstransitions

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with onset with onsetatat about about17, 17,about about72,72,about about 180180 and and about about 202The 202 °C. °C.TGAThe TGA curve curve in is shown is shown in 2023206094 18 Jul 2023

Figure 2727and Figure anddisplays displaysa weight a weight loss loss (about (about 6.0%6.0% RT toRT to about about 200 °C)200 °C) that wasthat was identified identified as as water based water based on on TGA-MS. Weight TGA-MS. Weight loss loss above above about about 250250 °C °C is is attributed to attributed to decomposition. The decomposition. The

dynamicvapor dynamic vapor sorption sorption curve curve indicates indicates that that the the formform absorbs absorbs about about 9 weight 9 weight % of % of water upwater to up to about 95% about RHatatabout 95% RH about25 25 °C. °C. XRPD XRPD analysisof ofthe analysis thesample sampleafter after the the DVS experimentshows DVS experiment shows that the that the material had not material had notchanged changed form. form.

Example 16. Example 16. Production Production of ofCompound Compound 11 Magnesium Form Magnesium Form II

[0485] Compound

[0485] Compound 1 Magnesium 1 Magnesium Form I Form I (hydrate) (hydrate) was prepared was prepared as follows. as follows. 987.6 987.6 milligrams milligrams

of anhydrous of FormII of anhydrous Form of Compound Compound 1 1was wasplaced placedininaa vial vial with with 156 156 milligrams milligrams of ofKOH and KOH and

about 1010mLmL about of of water. water. The The sample sample was sonicated was sonicated and until and heated heated theuntil the solution solution became became clear. clear. Next, 130milligrams Next, 130 milligramsof of magnesium magnesium acetate acetate tetrahydrate tetrahydrate was and was added, added, the and thewas sample sample was left to left to

stir atatroom stir temperaturefor room temperature forabout about3 days 3 days then then isolated. isolated. TheThe XRPDXRPD patternpattern of Compound of Compound 1 1 MagnesiumForm Magnesium Form I isshown I is shownininFigure Figure28. 28. The TheDSC DSC curve curve is isshown shownin inFigure Figure2929and andindicates indicates aa single endotherm single endotherm with with onset onset at about at about 53 °C. 53 °C. Thecurve The TGA TGAiscurve shown is inshown Figure in 30 Figure 30 and and displays displays a weight a loss (about weight loss (about13.8% 13.8%RT RT to about to about 150that 150 °C) °C) was thatidentified was identified as based as water water on based on TGA-MS. TGA-MS. Weightloss Weight lossabove above about about 250 250 °Cattributed °C is is attributed to decomposition. to decomposition. The dynamic The dynamic vapor vapor sorption sorption curve indicates curve indicatesthat that the the form formabsorbs absorbs about about 8 weight 8 weight % of% of water water up to up to about about 95% RH 95% RH 25 at about at about 25 °C. XRPD °C. XRPD analysis analysis of sample of the the sample after after theexperiment the DVS DVS experiment shows shows that that the had the material material not had not changed form. changed form. Example17. Example 17.Production Production of of Compound Compound 1 Diethanolamine 1 Diethanolamine Form IForm I

Compound

[0486] Compound

[0486] 1 Diethanolamine Form IForm 1 Diethanolamine I (hydrate) (hydrate) was prepared was prepared as follows. 106.9106.9 as follows. milligrams of milligrams of anhydrous anhydrous Form Form II of of Compound Compound 1 1 wasdissolved was dissolvedinin about about 33 mL of acetone. mL of acetone. 20 20 µL pL of diethanolamine of was diethanolamine was added, added, and and the sample the sample was sonicated was sonicated for2 about for about hours.2 An hours. An additional additional

about 4040µLpLofofdiethanolamine about diethanolamine was then was then added,added, and and the the sample sample further further slurriedslurried at room at room temperature and temperature and then then isolated. isolated.The TheXRPD pattern of XRPD pattern of Compound Compound 1 1Diethanolamine DiethanolamineForm Form I is I is

shownininFigure shown Figure31.31.TheThe DSCDSC curvecurve is shown is shown in Figure in Figure 32 and indicates 32 and indicates an endothermic an endothermic

transition with transition onset atat about with onset about118 118°C. °C.TheThe TGA TGA curve curve is shown is shown in 33 in Figure Figure 33 and displays and displays a a weightloss weight loss(about (about2.7% 2.7%RT RT to about to about 150that 150 °C) °C) was thatidentified was identified as water as water based based on on TGA-MS. TGA-MS. Weightloss Weight lossabove above about about 250 250 °Cattributed °C is is attributed to decomposition. to decomposition. The dynamic The dynamic vapor vapor sorption sorption curve indicates curve indicatesthat that the the form formabsorbs absorbs about about 14 wt. 14 wt. % of% of water water up toup to about about 95% RH95% RH at at about 25 about 25 °C. XRPD °C. XRPD analysis analysis of sample of the the sample after after theexperiment the DVS DVS experiment shows shows that that the had the material material not had not changed form. changed form. Example18. Example 18.Production Production of of Compound Compound 1 Piperazine 1 Piperazine Form Form I I

[0487] Compound

[0487] Compound 1 Piperazine Form Form 1 Piperazine I (hydrate) was was I (hydrate) obtained obtained as follows: as follows: anhydrous FormForm anhydrous I I of Compound of 1 was Compound 1 was placed placed in a centrifuge in a centrifuge tubeoneand tube and one ratio molar molarofratio of a piperazine a piperazine was alsowas also

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added. Next, added. Next,30 30 µlpl of of MeOH MeOH was to was added added to the powders, the powders, and thewassample and the sample wasfor sonicated sonicated about for about 2023206094 18 Jul 2023

30 minutes. 30 minutes. The The sample sample tube tube was was then then opened opened and and allowed allowed to to dry dry inina a nitrogen box. nitrogen The box. XRPD The XRPD

pattern of pattern ofCompound Compound 1 1Piperazine Piperazine Form FormII is is shown in Figure shown in Figure 34. 34. The The DSC curve is DSC curve is shown in shown in

Figure 3535and Figure andindicates indicatesmultiple multiple endothermic endothermic transitions transitions with with onsetonset 27 and27 at about at about and 139 about about 139 °C. The °C. TheTGATGA curve curve is shown is shown in Figure in Figure 36 and 36 and displays displays a weighta loss weight loss7.3% (about (about 7.3% RT to RT about to about 100 °C) 100 °C)that that was wasidentified identifiedasaswater waterbased based on on TGA-MS. TGA-MS. Weight Weight loss loss above above about 250 about °C is 250 °C is attributed to attributed to decomposition. The decomposition. The dynamic dynamic vaporvapor sorption sorption curve curve indicates indicates that that the theabsorbs form form absorbs about 1.5 about 1.5 wt. wt. %% ofof water water up up to to about about 95% 95% RH atRH at about about 25 °C. 25 °C.analysis XRPD XRPDofanalysis of the sample the sample after the after the DVS experiment DVS experiment shows shows that that the material the material hadchanged had not not changed form. form. Example19. Example 19.X-ray X-ray Powder Powder Diffraction Diffraction (XRPD) (XRPD) Analytical Analytical Method Method A A

[0488] XRPDXRPD

[0488] analysis analysis of amorphous of amorphous and Forms and Forms II, III, IV,IV, II, III, VI,VI, V, V, VII,and VII, VIIIofof andVIII Compound Compound 1 was 1 was carriedout carried outon onaa Siemens SiemensD5000 D5000diffractometer, diffractometer, scanning scanning the the samples samples between between

3 and 3 30degrees and 30 degrees20.20.Material Material was was gently gently compressed compressed on adisc on a glass glassinserted disc inserted into a into a sample sample holder. The holder. Thesample sample waswas thenthen loaded loaded intodiffractometer into the the diffractometer running running in reflection in reflection mode, mode, and the and the analysis was analysis wasconducted conducted using using the the following following experimental experimental conditions. conditions.

Raw DataOrigin Raw Data Origin Siemens-binary V2 Siemens-binary V2(.RAW) (.RAW) Start Position Start (°20) Position (°2) 3.0000 3.0000

End Position (°20) End Position (°2) 30.0000 30.0000

Step Size Step Size (°20) (°2) 0.0200 0.0200

Scan Step Scan Step Time (seconds) Time (seconds) 11 Scan Type Scan Type Continuous Continuous

Slit Types Slit Types Fixed Fixed

Divergence Slit Size Divergence Slit Size(mm) (mm) 2.0000 2.0000

Receiving SlitSize Receiving Slit Size(mm) (mm) 2.0000 2.0000

Detector Slit Size Detector Slit Size (mm) (mm) 0.2000 0.2000

Measurement Temperature Measurement Temperature (°C) (°C) 20.00 20.00

Anode Material Anode Material Cu Cu K-Alphal (A) K-Alphal (Å) 1.54060 1.54060

K-Alpha2 (A) K-Alpha2 (Å) 1.54443 1.54443

K-Beta (A) K-Beta (Å) 1.39225 1.39225

K-A2 K-A2 // K-A1 K-AlRatio Ratio 0.50000 (nominal) 0.50000 (nominal)

GeneratorSettings Generator Settings 40 mA, 40 mA, 40 40 kV kV

Focussing Circle Diameter Focussing Circle Diameter (mm) (mm) 401.00 401.00

Diffracted Diffracted Beam Monochromator Beam Monochromator Graphite Graphite

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Spinning Spinning No No 2023206094 18 Jul 2023

Example20. Example 20.X-ray X-ray Powder Powder Diffraction Diffraction (XRPD) (XRPD) Analytical Analytical Method Method B B

[0489] XRPDXRPD

[0489] analysis analysis of Form of Form of Compound I of ICompound was carried 1 was 1carried outa on out on PANalytical CubixCubix a PANalytical Pro diffractometer. Pro diffractometer.TheThe sample sample was was placed placed intosample into the the sample holder,holder, such such that thethat the of sample sample of Compound Compound 1 was 1 was levellevel with with the zero the zero height height forinstrument. for the the instrument. The following The following parameters parameters were were used to used to acquire acquirethe theXRPD pattern of XRPD pattern ofForm Form IIof ofCompound 1. Compound 1.

Start Position Start (°20) Position (°2) 3.0100 3.0100

End Position End Position (°20) (°2) 45.0100 45.0100

Input Step Input StepSize Size(°2) (°20) 0.03 0.03

Actual Step Actual Step Size Size (°20) (°2) 0.02 0.02

Time Per Time Per Step Step (seconds) (seconds) 10.1600 10.1600

Active Length Active (°20) Length (°2) 2.54 2.54

Scan Scan Mode Mode Continuous Continuous

Voltage (kV) Voltage (kV) 45 45

Current (mA) Current (mA) 40 40

Anode Anode Cu Cu ASS Primary ASS PrimarySlit Slit Fixed 1° Fixed 1°

DivergenceSlit Divergence Slit(Prog.) (Prog.) Automatic - 55 mm Automatic - - mm Soller Slits (RS) Soller Slits (RS) 0.02 radian 0.02 radian Scatter Slit Scatter Slit (PASS) (PASS) Automatic - 55 mm Automatic - - mm

Spinner Spinner 2 2

Example21. Example 21.X-ray X-rayPowder Powder Diffraction Diffraction (XRPD) (XRPD) Analytical Analytical Method Method C C

[0490] X-ray

[0490] X-ray powder powder diffraction diffraction (XRPD) (XRPD) analysis analysis of Compound of Compound 1 Sodium 1 Sodium Form I, Form I,

Compound Compound 1 Sodium 1 Sodium Form Form II, II, Compound Compound 1 Calcium 1 Calcium Form Form I, Compound I, Compound 1 Magnesium 1 Magnesium Form I, FormI, Compound Compound 1 Diethanolamine 1 Diethanolamine Form Form I, orCompound I, or Compound 1 Piperazine 1 Piperazine Form Form I was I was conducted conducted on aon a diffractometer (PANalytical diffractometer (PANalyticalXPERT-PRO, PANalytical XPERT-PRO, PANalytical B. B. V.,Almelo, V., Almelo,Netherlands) Netherlands)using using copper radiation copper radiation(Cu (Cu Kc, K, aX == 1.541874). 1.541874). Samples Sampleswere werespread spreadevenly evenlyononaa zero zero background background sampleplate. sample plate. The The generator generator was was operated operated at a voltage at a voltage of 45 of kV45 andkV and amperage amperage of 40 mA. of 40 mA. Slits Slits wereSoller were Soller0.02 0.02rad, rad,antiscatter antiscatter 1.0°, 1.0°, and anddivergence. divergence.Scans Scans werewere performed performed from 2 from to 2 to 40° 20 40° 20with witha a0.0167 0.0167 step step size.Data size. Data analysis analysis was was performed performed using X'Pert using X'Pert DataV1.2d Data Viewer Viewer V1.2d (PANalyticalB.V., (PANalytical B.V.,Almelo, Almelo, Netherlands). Netherlands).

Example22. Example 22.Thermogravimetric/Differential Thermogravimetric/Differential Thermal Thermal Analysis Analysis (TG/DTA) (TG/DTA)

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[0491] each analysis For analysis

[0491] For each as discussed as discussed in Examples 3 to 6 and3 8, in Examples of materialof and 8, 5 milligrams to 56 milligrams material was was 2023206094 18 Jul 2023

weighed into weighed into an an open open aluminum panand aluminum pan andloaded loadedinto into aa simultaneous simultaneous TG/DT analyzer and TG/DT analyzer and held held at at roomtemperature. room temperature.The sample The samplewas then at was then heated heated at of a rate arate of 10 from 10 °C/min °C/min from 25 °C 25 °C to 300 °C to 300 °C during which during whichtime time thethe change change in sample in sample weight weight was recorded was recorded along along with any with any differential differential thermal thermal events (DTA). events (DTA).Nitrogen Nitrogen was as was used used theaspurge the purge gas, atgas, at arate a flow flowofrate 100 of 100 cm3 cm³/min. /min.

[0492] For For

[0492] Examples Examples 2, 7, 2, 5, 9, 9,and 5, 7, TGAwaswas 18, TGA and1313toto18, used totoevaluate used sampleweight evaluatesample loss weightloss as aa function as of temperature function of temperaturebyby loading loading 1-10 1-10 milligrams milligrams of material of material onto aonto a an aluminum an aluminum weigh weigh pan(TA pan (TAInstruments, Instruments, NewNew Castle, Castle, DE)heated DE) and and heated the sample the sample to 350 °Ctoor350 °C at above or aabove at rate of a rate of 10 °C/min. 10 The sample °C/min. The sampleand andreference reference pans pans were under aa 60 were under 60 mL/min and40 mL/min and 40mL/min mL/minnitrogen nitrogen purge, respectively. purge, respectively. Data Data analysis analysis waswas completed completed using using Universal Universal Analysis Analysis 20004.7A 2000 Version Version 4.7A (TA Instruments, (TA Instruments, New Castle, DE). New Castle, DE).

Example23. Example 23.Differential DifferentialScanning ScanningCalorimetry Calorimetry (DSC) (DSC)

[0493] For each

[0493] each analysis For analysis as discussed as discussed in Examples to 11, 5 milligrams 8 to 11, 58 milligrams in Examples material of materialofwas was weighed into weighed into an an aluminum DSCpanpan aluminum DSC andsealed and sealednon-hermetically non-hermeticallywith withaa pierced pierced aluminum lid. aluminum lid.

Thesample The samplepanpan waswas thenthen loaded loaded into into a Seiko a Seiko DSC6200 DSC6200 (equipped(equipped with aand with a cooler), cooler), cooled and to cooled to and held and heldatat 25 25 °C. °C.Once Once a stable a stable heat-flow heat-flow response response was obtained, was obtained, the sample the sample and reference and reference

wereheated were heatedtotoapproximately approximately280 280 °Cdegradation °C (or (or degradation temperature temperature observedobserved byatTG/DTA) by TG/DTA) a at a scan rate scan rate of of 10 10 °C/min, °C/min,and andthetheresulting resulting heat heat flow flow response response was was recorded. recorded.

[0494] For For

[0494] Examples Examples 5, 7, 2, 5,2, 7, 9, 9,and 18, DSC and1313toto18, was DSCwas runbybyloading run loading1-5 milligramsofof 1-5milligrams material into material into aa crimped crimpedTzero Tzero standard standard aluminum aluminum pan pan and and heating heating theatsample the sample at 10from 10 °C/min °C/min from 20 to 20 to 300 300°C°Cororabove. above.TheThe sample sample and reference and reference pansunder pans were werea under a 50nitrogen 50 mL/min mL/minpurge. nitrogen purge. Dataanalysis Data analysiswas wascompleted completed using using Universal Universal Analysis Analysis 2000 Version 2000 Version 4.7A (TA 4.7A (TA Instruments, Instruments,

New Castle, DE). New Castle, DE). Example24. Example 24.Karl-Fischer Karl-Fischer Coulometric Coulometric Titration Titration (KF) (KF)

[0495] Prior

[0495] Prior to to analyzing analyzing a acompound compound sample, sample, a blank a blank sample sample containing containing methanol methanol only only waswas

analyzedusing analyzed usinga aMettler Mettler Toledo Toledo C30 C30 Compact Compact Titrator, Titrator, to determine to determine thewater the blank blank water content. content. Approximately Approximately 10-15 10-15 milligrams milligrams of solid of solid material material was accurately was accurately weighed weighed into The into a vial. a vial. The material was material wasthen thendissolved dissolved in in methanol methanol and and the amount the amount added added was was recorded. recorded. The resultant The resultant was was then manually then manuallyintroduced introduced intointo thethe titrationcell titration cellofofthetheinstrument. instrument.The The water water content content was was calculated asas aa percentage calculated percentageandand thethe value value recorded. recorded.

Example25. Example 25.Infrared Infrared Spectroscope Spectroscope (IR) (IR)

Infrared

[0496] Infrared

[0496] spectroscopy waswas spectroscopy carriedoutoutonona aBruker carried ALPHA BrukerALPHA P spectrometer. P spectrometer. Sufficient Sufficient

material was material wasplaced placedonto onto thethe center center of of thethe plate plate of of thethe spectrometer spectrometer and and the spectra the spectra were were obtainedusing obtained usingthe thefollowing following parameters. parameters.

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1 Resolution (cm- (cm¹) ) 4 4 2023206094 18 Jul 2023

BackgroundScan Background ScanTime Time (scans) (scans) 16 16

Sample Scan Sample ScanTime Time(scans) (scans) 16 16

Data Collection Data Collection Range (cm¹)1) Range (cm- 4000-400 4000 400

Result Spectrum Result Spectrum Transmittance Transmittance

Software Software OPUSv.6 OPUS v.6

Example 26. Example 26. Dynamic Vapor Sorption Dynamic Vapor Sorption (DVS) (DVS)

[0497] For For

[0497] DVS DVS analysis analysis as discussed as discussed in in Example Example 8, approximately 8, approximately 10 milligrams 10 milligrams of of sample sample was placedinto was placed intoa amesh mesh vapor vapor sorption sorption balance balance panloaded pan and and loaded into a into DVS-1a dynamic DVS-1 vapor dynamic vapor sorption balance sorption balance (Surface (SurfaceMeasurement Systems). The Measurement Systems). The sample samplewas wassubjected subjected to to aa ramping ramping

profile from00-90% profile from -90% relativehumidity relative humidity (RH)(RH) at increments, at 10% 10% increments, maintaining maintaining theatsample the sample each at each step until step until aa stable stable weight hadbeen weight had beenachieved achieved (99.5% (99.5% step step completion). completion). After completion After completion of the of the sorption cycle, sorption cycle, the the sample samplewas was dried dried using using the the reverse reverse procedure, procedure, lowering lowering the RH the to RH to 0%. 0%. The The weight change weight change during during thethe sorption/desorption sorption/desorption cycles cycles was plotted. was plotted.

[0498] For For

[0498] Examples 5, 7, 2, 5,2, 7, Examples and1313toto18, 9, 9,and hygroscopicity was 18, hygroscopicity using dynamic studied using was studied dynamic

vapor vapor sorption sorption (DVS, (DVS, TA Q5000SA,SA,TATA TA Q5000 Instruments,New Instruments, New Castle, Castle, DE DE or or DVS, DVS, DVS DVS Intrinsic, Intrinsic,

Surface Measurement Surface Systems,London, Measurement Systems, London,UK). UK).A sample A sample (2-20 (2-20 mg) mg) was was placed placed in aluminum in an an aluminum DVSpanpan DVS andand loaded loaded on sample on the the sample side side of theof the pan twin twinbalance. pan balance. Thesorption The water water sorption and and desorptionwere desorption werestudied studied as as a function a function of of relative relative humidity humidity (RH)(RH) at 25 at 25 In°C.10%InRH10% °C. RH increments, the increments, therelative relativehumidity was humidity increased was from increased 5%5%RH from to95% RH to 95% RH and then RH and then decreased backtoto 5%. back 5%.Each Each relative relative humidity humidity increment increment had anhad an equilibration equilibration time oftime of 180 minutes, 180 minutes, unless unless weight change weight change %%was wasless less than than 0.002% in 30 0.002% in 30 minutes. minutes. Data Data analysis analysis was was performed using performed using

Universal Analysis Universal Analysis 2000 2000 Version 4.7A (TA Instruments, 4.7A (TA Instruments, New Castle, DE) New Castle, for TA DE) for DVSruns TA DVS runsand and Microsoft Excel for Microsoft for SMS DVSruns. SMS DVS runs. Example27. Example 27.High High Performance Performance Liquid Liquid Chromatography Chromatography - Ultraviolet - Ultraviolet Detection Detection (HPLC- (HPLC UV). UV).

[0499]

[0499] Purity Purity and analyses concentrationanalyses andconcentration were were carried carried out using out using the following the following method: method:

Instrument Instrument Agilent 1100 1100

Column Column Waters XBridge Waters XBridgeC18 C183.5µ 3.5p150 150x x3 3mmmm ColumnTemperature Column Temperature(°C) (°C) 40 40

AutosamplerTemperature Autosampler Temperature(°C) (°C) 20 20

UV Wavelength UV Wavelength (nm) (nm) 315 315

Injection Volume Injection (pL) Volume (µL) 5 5

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Flow Rate Flow Rate (mL/min) (mL/min) 0.8 0.8 2023206094 18 Jul 2023

Mobile Phase AA Mobile Phase 0.05%TFA 0.05% TFAininwater water Mobile Phase BB Mobile Phase 0.05 TFA 0.05 TFA in in acetonitrile acetonitrile

Gradient Program Gradient Program Time (min) Time (min) Solvent B Solvent (%) B (%)

0.0 0.0 25 25

25.0 25.0 75 75

30.0 30.0 95 95

35.0 35.0 95 95

35.1 35.1 25 25

40.0 40.0 25 25

Example 28. Example 28. pKa pKa Measurements Measurements

[0500] pKa pKa

[0500] was was analysis analysis performed performed using using a UV-metric a UV-metric method. method. The sample The sample was titrated in ain was titrated a triple titration triple titration(pH (pH 12.1 12.1 to pH 2) at pH 2) at concentrations concentrationsofof3232toto2020µM pM under under methanol-water methanol-water co- co solvent conditions solvent conditions(the (themethanol methanol concentration concentration varied varied from from 53 -(v/v). 53 - 30% 30% The (v/v). pKa The was pKa was determinedusing determined using the the spectroscopic spectroscopic datadata by aby a Yasuda-Shedlovsky Yasuda-Shedlovsky extrapolation extrapolation of the of the results results fromeach from eachtitration. titration. Example 29. Example 29. LogP LogP and and LogD LogDDetermination Determination

[0501] LogPLogP

[0501] analysis was was analysis performed performed using using a potentiometric a potentiometric (pH-metric) (pH-metric) method. The The method. samplewas sample was titratedininvarious titrated variousratios ratiosofofoctanol/water octanol/water in in twotwo titrations titrations covering covering the the pH range pH range

from1.9 from 1.9toto 12.0 12.0atat concentrations concentrationsofof 1.01.0 toto0.6 0.6mM. mM. The shift The shift ofaqueous of the the aqueous pKa inpKa the in the presenceofofoctanol presence octanolwas was used used to determine to determine logP logP ofneutral of the the neutral and anionic and anionic species. species. From From this this informationa alipophilicity information lipophilicityprofile profilewas wasconstructed, constructed, such such that that that that logD logD at aatgiven a given pH could pH could be be determined. determined.

Example30. Example 30.Pharmaceutical Pharmaceutical Composition Composition

[0502] A pharmaceutical

[0502] A pharmaceutical composition composition comprising I of ICompound Form Form comprising of Compound was prepared 1 was 1prepared that that contains the contains the following followingingredients. ingredients. Ingredient Ingredient Quality Standard Quality Standard Capsule Strength Capsule Strength

10 mg 10 mg 50 mg 50 mg 200 mg 200 mg

Compound Compound 1 (Form 1 (Form I)I) In-house In-house 17.00 gg 17.00 110.0 gg 110.0 640.0 gg 640.0

Gelucire@ 50/13 Gelucire® 50/13(stearoyl (stearoyl macrogol- macrogol- USP/NF,Ph. USP/NF, Ph.Eur. Eur. 153.00 gg 153.00 198.0 gg 198.0 288.0 gg 288.0

32 glycerides; 32 glycerides; surfactant) surfactant)

Fast Flo@ Fast 316(lactose FloR 316 (lactose monohydrate; monohydrate; NF NF 556.75 g 556.75 g 632.5 gg 632.5 440.0 gg 440.0

filler) filler)

Ac-Di-Sol@SD-711 Ac-Di-Sol® SD-711 (croscarmellose (croscarmellose NF, Ph.Eur., NF, Ph. Eur.,JPJP 38.25 gg 38.25 49.5 gg 49.5 72.0 gg 72.0

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sodium,disintegrant) sodium, disintegrant) 2023206094 18 Jul 2023

TheoreticalBatch Theoretical BatchSize Size (g)(g) 765.00 gg 765.00 990.0 gg 990.0 1440.0 gg 1440.0

TheoreticalBatch Theoretical BatchSize Size (# (# capsules) capsules) 1700 1700 2200 2200 3200 3200

[0503] The The

[0503] pharmaceutical pharmaceutical composition was was composition prepared prepared as follows. as follows.

Example31. Example 31.Micronization Micronization

[0504] Crystalline

[0504] Crystalline Compound Compound 1 (Form I)1 was (Form I) was continuously continuously fed into a 2 fed inchinto a 2 inch vertical loopvertical jet loop jet mill. The mill. Thecompressed compressedair air supply supply was was high high puritypurity nitrogen, nitrogen, with with an an pressure inlet inlet pressure of at 110 of at least least 110 p.s.i. p.s.i. The pushernozzle The pusher nozzleandand grinder grinder nozzle nozzle pressures pressures were were both maintained both maintained at 80 p.s.i. at 80 p.s.i.

throughoutthe throughout themilling millingprocess. process. TheThe feedfeed rate rate was was controlled controlled by a vibratory by a vibratory feeder, feeder, at an at an equipmentsetsetpoint equipment pointofof 3.3.Approximately Approximately 800 grams 800 grams of material of material was generated was generated over the over the course course of approximately of approximately5 hours 5 hours in thismanner. in this manner. This This material material wascollected was then then collected in a single in a single container container

and mixed and mixedprior priortotoincorporation incorporation into into thethe hothot melt melt granulations granulations at 10atmilligrams, 10 milligrams, 50 milligrams, 50 milligrams,

and 200 and 200milligrams milligrams dosage dosage strengths. strengths.

Example32. Example 32.Hot Hot Melt Melt High High Shear Shear Granulation, Granulation, Milling, Milling, and and Blending Blending

[0505] The The

[0505] granulations granulations were were prepared prepared in jacketed in a on on L bowl a jacketed4L4 bowl a Vector GMXGMX a Vector Lab-Micro Lab-Micro

HighShear High Sheargranulator. granulator.The The bowlbowl was jacketed was jacketed withatwater with water at Approximately 60 °C. 60 °C. Approximately half of the half of the lactose monohydrate, lactose monohydrate, croscarmellose croscarmellose sodium, sodium, and and the themicronized micronized Compound Compound 1 1drug drugsubstance substance were added to were added to the the bowl. bowl. The remaining lactose The remaining lactose was was then then used used totodry drywash washthe Compound the Compound 1 drug 1 drug

substancetransfer substance transfercontainer containerprior priortotoaddition additiontotothe thebowl. bowl. TheThe dry,dry, solid solid components components were were then then mixeduntil mixed untilthe theblend blendreaches reaches 55 55 °C.°C. OnceOnce this temperature this temperature is reached, is reached, the Gelucire the Gelucire 50/13 50/13 melted, and melted, andthe thegranulation granulationcontinued continued mixing mixing untiluntil the product the product temperature temperature drop occurred drop occurred as the as the Gelucire50/13 Gelucire 50/13melts. melts.TheThe granulation granulation continued continued mixingmixing until until the the product product temperature temperature

recoveredtoto5555°C°Cto toensure recovered ensure complete complete melting melting and mixing and mixing of the of the Gelucire Gelucire 50/13. 50/13. This This granulatedproduct granulated productwaswas then then allowed allowed to cool to cool to room to room temperature. temperature. Thegranulation The cooled cooled granulation was was milled using milled usinga aQuadro Quadro Comil Comil 197S 197S equipped equipped with a with a 1905 1905 µm screenpm andscreen a roundand a round impeller. impeller. Example33. Example 33.Capsule Capsule Preparation Preparation

[0506] The The

[0506] powder powder prepared prepared in Example in Example 22 was usingusing was encapsulated 22 encapsulated a Profill a Profill apparatus into apparatusinto size 00 white size opaquegelating white opaque gelating capsules, capsules, which which werewere then then dedusted. dedusted. Thecapsule The final final capsule drug drug producthad product hada afill fill weight weightofof450 450mg,mg, of of which which 90 milligrams 90 milligrams was Gelucire was Gelucire 50/13, 50/13, 22.5 22.5 milligramswas milligrams wascroscarmellose croscarmellose sodium, sodium, andremaining and the the remaining weight weight was was comprised comprised of lactose of lactose monohydrateand monohydrate andmicronized micronizedCompound Compound 1 drug 1 drug substance. substance. TheThe amount amount of each of each of lactose of lactose

monohydrateand monohydrate andCompound Compound 1 was 1 was dependent dependent on the on the dosage dosage strength,with strength, withtheir their combined combined weightequal weight equaltoto337.5 337.5totoachieve achieve a total450450 a total milligrams milligrams fill fill weight. weight. A weight A 100% 100% weight sort wassort was

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carried out, carried out, and the final and the final product waspackaged product was packaged in white in white opaque opaque HDPE bottles, HDPE bottles, which which were thenwere then 2023206094 18 Jul 2023

induction sealed. induction sealed. Example34. Example 34.Synthesis Synthesis ofof Intermediate Intermediate(R)-G-1-a (R)-G-1-a 0 O OOH OH O O CHO CHO O O vinyl vinyl Oo O O O O butyrate O butyrate o

rac-G-7-a rac-G-7-a rac-G-5-a rac-G-5-a (R)-G-8-a (R)-G-8-a

OH OH OMs OMs Br Br

O O O0 S0 O O O0 'N o

(R)-G-5-a (R)-G-5-a (R)-G-6-a (R)-G-6-a (R)-G-1-a (R)-G-1-a

Step 1.1. Synthesis Step Synthesisofofrac-G-7-a rac-G-7-a

[0507] A 1000

[0507] A 1000 L reactor L reactor was was charged charged withwith 330 330 kg DMSO, kg DMSO, and potassium and potassium t-butoxide t-butoxide (30 (30 kg, kg, 1.22 eq) 1.22 eq) were wereadded addedat at 10-25 10-25 °C.°C. Trimethylsulfoxonium Trimethylsulfoxonium iodide iodide (58 (58 eq) kg, 1.2 kg, was 1.2 added eq) was in added in several portions several portions atat 18-25 18-25°C, °C,and andthethemixture mixture was was stirred stirred in that in that temperature temperature rangerange forhours. for two two hours. 2-Methoxybenzaldehyde 2-Methoxybenzaldehyde (30.15(30.15 kg,eq)1.0 kg, 1.0 waseq) wasinadded added in portions several several portions while maintaining while maintaining the the reactor temperature reactor temperaturebetween between 18-25 18-25 °C. mixture °C. The The mixture was at was stirred stirred at a temperature a temperature between between 18-25 18-25 °C until °C until 2-methoxybenzaldehyde wasdetermined 2-methoxybenzaldehyde was determinedtoto be be present present at at less lessthan 0.5% than 0.5%bybyHPLC HPLC

(typically 1-2 (typically 1-2 hours), hours), whereupon whereupon 300 300 kg water kg water was added was added to quench to quench the reaction, the reaction, maintaining maintaining

the temperature the temperaturebelow below 25 25 °C. °C. The reaction The reaction mixture mixture was extracted was extracted with (3 with heptane heptane (3 of portions portions of 204kg), 204 kg), and andthe theheptane heptane extracts extracts were were combined, combined, washedwashed with(3water with water (3 portions portions of 300 of 300 kg), kg), then brine then brine (300 (300kg). kg). TheThe organic organic layer layer was was concentrated concentrated under under vacuum vacuum at 40-45 at °C,40-45 °C, affording affording rac-G-7-a (18.55 rac-G-7-a (18.55 kg, kg, 56% isolated yield, 56% isolated yield,HPLC HPLC purity purity96.6% 96.6% at at220 220 nm, nm, 94% wt. by 94% wt. by NMR) NMR) asas

an oil, an oil, which wasused which was usedin inthethenext nextstep stepwithout without any any further further purification. purification.

Alternative Step Alternative Step 1: 1: Synthesis Synthesis of rac-G-7-a of rac-G-7-a

To 2-methoxybenzaldehyde

[0508] To 2-methoxybenzaldehyde

[0508] eq) added (1 eq)(1 was was added trimethylsulfonium trimethylsulfonium methyl methyl sulfate sulfate

(1.08 eq), (1.08 eq), followed followedbybydichloromethane dichloromethane (about (about 75.5 and 75.5 mL), mL),theand the resulting resulting mixturemixture was agitated. was agitated.

Tothe To the mixture mixturewas was added added ca. ca. 50 wt% 50 wt% aqueous aqueous NaOHwise NaOH portion portion wise and and stirred for stirred for about 2.5 about 2.5 hoursatat aa temperature hours temperaturerange range of of about about 28 28 °Cabout °C to to about 22 Additional 22 °C. °C. Additional water water was and was added, added, the and the mixturecooled mixture cooledto toa atemperature temperature of about of about 17 Dichloromethane 17 °C. °C. Dichloromethane was was added to added to theand the mixture mixture and stirred. The stirred. mixturewas The mixture wasseparated, separated, andand thethe organic organic layer layer was was concentrated concentrated under vacuum, under vacuum, to to provide rac-G-7-a. rac-G-7-a. 'H ¹H NMR (400MHz, NMR (400 MHz, CDC3): CDCl): 6 7.28-7.25 7.28-7.25 (m, 1H), (m, 1H), 7.157.15 (d, (d, J =J= 7.57.5 Hz,1H), Hz, 1H),

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1004799942

6.94 (t, J= 6.94 (t, 7.5 Hz, J = 7.5 Hz, 1H), 6.88(d, 1H),6.88 (d, JJ= 8.2Hz, = 8.2 Hz,1H), 1H),4.21 (t,(t,J J= 4.21 = 2.92.9 Hz,Hz, 1H), 1H), 3.873.87 (s, (s, 3H),3H), 3.143.14 (t, (t, 5.6,2.42.4Hz,Hz, 2023206094 18 Jul 2023

J= 4.9 Hz, = 4.9 Hz,1H), 1H),2.71 2.71(dd, (dd,J =J= 5.6, 1H). 1H).

Step 2.2. Synthesis Step Synthesisofofrac-G-5-a rac-G-5-a

[0509] Tetrahydro-2H-pyran-4-ol

[0509] Tetrahydro-2H-pyran-4-ol (16.3 (16.3 kg, kg, 4.04.0 eq)eq) waswas charged charged intoa a5050L Lreactor, into reactor, followedbybyFeCl followed (225(225 FeCl3 g, 0.035 g, 0.035 eq). eq). Intermediate Intermediate rac-G-7-a rac-G-7-a (6.0 kg,(6.0 1.0 kg, 1.0 eq) eq) was was added added dropwise,maintaining dropwise, maintainingthethe temperature temperature between between -10 to-10 to 10 10 °C. The°C. The reaction reaction wasatstirred was stirred at between0-10 between 0-10°C °C until until thethe startingepoxide starting epoxide was was shownshown to be to be present present at lessatthan less 0.5% thanby0.5% HPLCby HPLC (typically 0.5-1 (typically 0.5-1 hours). hours). Once Oncethethe reaction reaction waswas judged judged to betocomplete, be complete, the reaction the reaction mixture mixture was was diluted with diluted with toluene toluene(240 (240andL),theand the toluene toluene solution solution was extracted was extracted with with water (3 water (3 of portions portions 24 of 24 kg), then kg), brine (12 then brine (12 kg). kg). The The organic organic layer layer waswas concentrated concentrated under under vacuum vacuum between between 40-45 °C, 40-45 °C, affording rac-G-5-a affording rac-G-5-a(19.64 (19.64 kg, kg, 47% 47% yield) yield) as anasoil. an oil. Alternative Step Alternative Step 2: 2: Synthesis Synthesis of rac-G-5-a of rac-G-5-a

[0510] Toluene

[0510] Toluene is charged is charged to to a reactor, followed a reactor, followed by by tetrahydro-2H-pyran-4-ol tetrahydro-2H-pyran-4-ol (4 (4 eq), eq),BF3 BF-

Et20(0.005 Et2O . Intermediate v/w)Intermediate (0.005 v/w). rac-G-7-a rac-G-7-a (1.0iseq) (1.0 eq) is added added dropwise, dropwise, maintaining maintaining the the temperaturebetween temperature between0 to0 10 to °C. 10 °C. The The reaction reaction is stirred is stirred for for about about an hour an hour at a temperature at a temperature

between0 0toto1010°C.°C.TheThe between solution solution is combined is combined with with toluene toluene (about (about 8 v/w) 8atv/w) aboutat15 about to 2515°Cto 25 °C and washed and washedwith with water water about about three three times. times.The Thewater waterlayers areare layers combined, washed combined, washedwith withMTBE, MTBE,

and the and the MTBE MTBE layers layers are are washed washed with about with water water two about twoThe times. times. Thelayers organic organic are layers then are then combinedandand combined concentrated concentrated under under vacuum. vacuum. To the To the resulting resulting residue,residue, THF isandadded, THF is added, the and the mixtureisis concentrated mixture concentratedunder under vacuum, vacuum, affording affording rac-G-5-a rac-G-5-a as ansolution. as an stock stock solution. Step 3.3. Synthesis Step Synthesisofof(R)-G-5-a (R)-G-5-a

[0511] A 50AL50glass

[0511] L glass reactor reactor waswas charged charged with with toluene toluene (5.0v/w), (5.0 v/w),followed followedbybyrac-G-5-a rac-G-5-a(6.2 (6.2 kg, 1.0 eq) kg, 1.0 eq) inin one oneportion. portion.TheThe solution solution was was warmed warmed to 40 °Ctountil 40 °Ctheuntil the became mixture mixturea clear became a clear solution, then solution, then cooled cooledtoto2525°C.°C. Vinyl Vinyl butyrate butyrate (0.5waseq)added (0.5 eq) wasinadded in onetoportion one portion to the above the above solution, and solution, andthe themixture mixturewaswas stirred stirred for hours for 0.5 0.5 hours at a temperature at a temperature between between 25-30a 25-30 °C until °C until a clear solution clear solution was wasobtained. obtained.CAL-B CAL-B lipase lipase (1.5%wasw/w) (1.5% w/w) addedwas added in one in one portion portion to the to reactor the reactor and the and the mixture mixture was wasstirred stirred at at 22-26 22-26 °C °C until until the the reaction reaction was deemedcomplete was deemed complete when when IPC IPC showedthe showed theratio ratio of of (S)-G-5-a (S)-G-5-a // (R)-G-5-a (R)-G-5-a was was96:3.5 96:3.5and andthethee.e. e.e. ofof(R)-G-8-a (R)-G-8-awas was97.9% 97.9% (typically 44 hours). (typically hours). The TheCAL-B CAL-B was filtered was filtered out,the out, and andfilter the filter cake cake washedwashed with THFwith THF (11.6 L). (11.6 L). The filtrate The filtrate was was combined withthat combined with that ofofanother anotherbatch batchofofthe thesame samescale, scale,and andthethecombined combined filtrates were filtrates were concentrated undervacuum concentrated under vacuum at 35-40 at 35-40 °C until °C until 13 residue 13 L of L of residue remained. remained. PetroleumPetroleum

ether (5.0 ether (5.0 v/w) v/w)was was added, added, and and the mixture the mixture stirred stirred for 30for 30 minutes. minutes. The precipitated The precipitated (S)-G-5-a (S)-G-5-a was filtered, and was filtered, the filter and the filter cake cake washed with petroleum washed with petroleumether ether(2.0 (2.0v/w). v/w). TheThe filtratewas filtrate was concentratedunder concentrated under vacuum vacuum at a at a temperature temperature between between 40-45 40-45 °C, °C, resulting resulting in oil. in a crude a crude oil. Toluene Toluene (3.0 v/w) (3.0 wasadded v/w) was added to to a 50 a 50 L glass L glass reactor, reactor, followed followed by oil by the the from oil from the previous the previous step. step. Succinic Succinic

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1004799942

anhydride (0.25 anhydride (0.25 eq.) eq.)and and dimethylaminopyridine dimethylaminopyridine (DMAP, 0.02eq.) (DMAP, 0.02 eq.) were were added, added, and and the the mixture mixture 2023206094 18 Jul 2023

was heated was heated toto between between70-80 70-80°C °C and and stirred stirred forfor twotwo hours, hours, sampling sampling periodically periodically until until thethe

amount of amount of (S)-G-5-a (S)-G-5-a remaining remaining was was no no more morethan than 0.5% 0.5%bybyHPLC. HPLC.TheThe mixture mixture was was thenthen cooled cooled

to between to 10-20 °C between 10-20 °Cand andwashed washed with with saturatedaqueous saturated aqueoussodium sodium bicarbonate bicarbonate (two (two portions portions of of

1.0 v/w). 1.0 HPLC v/w). HPLC analysis analysis of organic of the the organic layer layer showedshowed that that the the of amount amount of (S)-G-5-a (S)-G-5-a present waspresent was less than less 0.1%.TheThe than 0.1%. organic organic solvent solvent was concentrated was concentrated to give to an give an oil oil (9.9 kg,(9.9 kg,yield, 53.6% 53.6%89%yield, 89% purity, 97% purity, e.e.) which 97% e.e.) was used which was usedininthe the next next step step without without further further purification. purification. To To aa 100 100 LL reactor was reactor added methanol was added methanol(40 (40L), L),followed followedbybythetheoil oil from fromthe theprevious previousstep, step, followed followed byby water (30 water (30kg, kg,3.0 3.0w/w). w/w). Sodium Sodium hydroxide hydroxide (1.23 (1.23 kg) kg) in portions in several several portions while maintaining while maintaining the the temperaturebetween temperature between 10-25 10-25 °C. reaction °C. The The reaction was stirred was stirred at thatattemperature that temperature untilanalysis until HPLC HPLC analysis indicated that indicated that the the butyrate butyrateester esterwas wascompletely completely consumed. consumed. Theadjusted The pH was pH was toadjusted 7 with 3toN 7 with 3 N aqueous HCl, aqueous HCl, and andthe the mixture mixture was was concentrated concentrated at at vacuum vacuumbetween between40-45 40-45°C°C until3030volumes until volumes remained.TheThe remained. mixture mixture was filtered was filtered and and the the filter filter cake cake was was collected collected to give to give crude crude (R)-G-5-a (R)-G-5-a (9.0 kg, (9.0 96%purity, kg, 96% purity,96.8% 96.8% e.e.).Ethyl e.e.). Ethyl acetate acetate (4.3(4.3 L) petroleum L) and and petroleum ether ether (26 L) (26 wereL) were charged charged into aa reactor, into reactor, followed bythe followed by thecrude crudeproduct product from from the the previous previous step.step. The mixture The mixture was stirred was stirred for for 1 hour 1 at aa temperature hour at temperature between between 10-2510-25 °C,filtered. °C, then then filtered. The collected The collected solids solids were driedwere in a dried in a vacuumoven vacuum ovenatatbetween between40-45 40-45 °C,°C, yieldingpure yielding pure(R)-G-5-a (R)-G-5-a (5.2 (5.2 kg,kg, 70%70% yield yield for for thisstep, this step, 99%purity, 99% purity,96% 96% e.e.) e.e.) as as an an off-white off-white solid. solid.

Alternate Step Alternate Step 3: 3: Alternate Synthesis of Alternate Synthesis of (R)-G-5-a (R)-G-5-a

0 HOOO OH HO HOO OH 0 0 0 0 0 O O O O O O (R)-G-5-a (R)-G-5-a

rac-G-5-a rac-G-5-a (R)-G-8-b (R)-G-8-b

[0512] A 50A L50glass

[0512] L glass reactor reactor waswas charged charged with with THFTHF (29 (29 L),L), followed followed by by rac-G-5-a rac-G-5-a (5.8kg, (5.8 kg, 1.0 eq) 1.0 eq) in in one portion. Succinic one portion. Succinicanhydride anhydride (2.3(2.3 kg, kg, 1.0 1.0 eq) eq) was was addedadded in oneinportion one portion to the to the abovesolution, above solution,and andthethemixture mixture waswas stirred stirred forfor 0.50.5 hours hours at aattemperature a temperature between between 25-30 25-30 °C °C until aa clear until clear solution solution was obtained.CAL-B was obtained. CAL-B lipase lipase (406 (406 g, 7% g,w/w) 7%was w/w) wasin added added in onetoportion one portion to the reactor the and the reactor and the mixture mixturewas was stirredatat25-30 stirred 25-30 °C °C until until thethe reaction reaction waswas deemed deemed complete complete

(whenthe (when theratio ratio ofofG-5-a G-5-ato to(R)-G-8-b (R)-G-8-b was was shownshown to be by to be 51:49 51:49 by IPC (typically IPC (typically 24 The 24 hours). hours). The CAL-Bwas CAL-B wasfiltered filtered out, out, and and the thefilter cake filter washed cake with washed THF with THF(11.6 L).TheThe (11.6 filtrates were filtrates were

combinedandand combined concentrated concentrated under under vacuum vacuum at 35-40at°C. 35-40 The °C. The resulting resulting residue residue was was diluted diluted with with ethyl acetate ethyl acetate (58 (58 L) L) atat 15-25 15-25°C, °C,and andthetheethyl ethylacetate acetatewaswas washed washed with with saturated saturated sodiumsodium

bicarbonate(four bicarbonate (fourportions portionsofof2323L) L) at at 15-25 15-25 °C.°C. A sample A sample from from the the acetate ethyl ethyl acetate layer layer was was

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analyzedbybyHPLC, analyzed HPLC, which which indicated indicated thatratio that the the ratio of (R)-G-8-b of (R)-G-8-b to was to G-5-a G-5-a was than no more no more 1:99. than 1:99. 2023206094 18 Jul 2023

Theaqueous The aqueous layers layers were were combined combined and washed and washed with with ethyl ethyl (three acetate acetateportions (three portions of 29 L).of A 29 L). A samplefrom sample from theaqueous the aqueous layer layer was was analyzed analyzed by which by HPLC, HPLC,indicated which indicated that the that the ratio ratio of of (R)-G- (R)-G 8-b to 8-b to G-5-a G-5-awas was greater greater than than 99.5:0.5. 99.5:0.5. To aqueous To the the aqueous layer layer was sodium was added added hydroxide sodium hydroxide (5.8 (5.8 kg) in kg) in several several portions portionsatat aa temperature temperaturebetween between 15-25 15-25 °C. reaction °C. The The reaction was stirred was stirred at thatat that temperatureforfor0.5-1 temperature 0.5-1hours, hours,until untilHPLC HPLC analysis analysis indicated indicated that that the ratio the ratio of (R)-G-8-b of (R)-G-8-b to (R)-G to (R)-G-

5-a was 5-a wasnonogreater greaterthan than1:99. 1:99.TheThe reaction reaction mixture mixture was filtered, was filtered, andfilter and the the filter cake cake was washed was washed

with water with water(5.8L). (5.8 L).TheThe filter filter cake cake waswas dried dried at 40-45 at 40-45 °C to°C to constant constant weight, weight, yielding yielding 2.4 kg 2.4 of kg of crude (R)-G-5-a crude (R)-G-5-awith with 96% 96% purity purity and 98.9% and 98.9% e.e. material e.e. Crude Crude material from batches from multiple multiplewasbatches was purified by purified by recrystallization recrystallization as as follows. follows. Into Intoa a100 100L reactor L reactor containing containing ethyl ethyl acetate acetate (726 L, (72 L, 6 volumes), was volumes), charged crude was charged crude (R)-G-5-a (R)-G-5-a (12 (12 kg), kg), and and the the mixture mixturewas waswarmed to 30-35 warmed to 30-35 °C °C and and

stirred for stirred for 11 hour. Thesolution hour. The solutionwas was filteredtotoremove filtered remove undissolved undissolved solids, solids, andfiltrate and the the filtrate was was concentratedunder concentrated under vacuum vacuum at 40-45 at 40-45 °C until °C until approximately approximately two volumes two volumes of solventof solvent remained. remained. Tothis To this solution solution was wasadded added heptanes heptanes (120(120 L, 10L,volumes), 10 volumes), and and the the mixture mixture wastoheated was heated refluxto reflux to obtain to obtain aa clear clear solution. solution. The Thesolution solutionwaswas cooled cooled to atotemperature a temperature between between 15-20 15-20 °C °C gradually gradually

over eight over eight hours, hours, and andstirred stirredfor for1212hours hoursatatthat thattemperature. temperature.TheThe resulting resulting solids solids werewere

collected by collected by filtration, filtration, and the filter and the filter cake cake was washedwith was washed with a solution a solution of of ethyl ethyl acetate/heptanes acetate/heptanes

(1:5, 12 (1:5, 12 L) L) once. once. The The cake cake waswas collected collected and dried and dried at 40-45 at 40-45 °C to °C to constant constant weight,weight, providing providing

10.2 kg 10.2 kg of of(R)-G-5-a (R)-G-5-a(99.2% (99.2% purity purity by HPLC, by HPLC, 99.8% 99.8% e.e.) as e.e.) as an off-white an off-white solid. solid. Synthesis

[0513] Synthesis

[0513] of (R)-G-5-a of (R)-G-5-a alsoalso waswas carried outsimilar carriedout to the similar to the method described above method described above

with Novozyme with 435ininplace Novozyme 435 placeof of CAL-B CAL-B lipase. lipase.

Step 4. Step 4. Synthesis Synthesis of of (R)-G-6-a (R)-G-6-a

[0514] IntoInto

[0514] a 100 a 100 L glass L glass reactorunder reactor undernitrogen, nitrogen, was was charged charged dichloromethane dichloromethane (58L) (58 L) followedbyby(R)-G-5-a followed (R)-G-5-a (5794 (5794 g, eq.), g, 1.0 1.0 eq.), and and triethylamine triethylamine (4.8the (4.8 and L),reaction and the mixture reactionwasmixture was cooled toto between cooled between 0-10 0-10 °C.°C. Methanesulfonyl Methanesulfonyl chloride chloride (3160 (3160 g) g) was over was charged charged over 35 35 minutes, minutes, maintainingthe maintaining thereaction reactiontemperature temperature no higher no higher than than 25 Then 25 °C. °C. the Then the mixture mixture wasatstirred was stirred at between 20-30 between 20-30 °C °Cfor for 18 18 hours, hours, whereupon the amount whereupon the of (R)-G-5-a amount of (R)-G-5-a remaining remaining was wasdetermined determined to be to no more be no morethan than1%.1 Purified Purified water water (58wasL)added, (58 L) was added, and theand the mixture mixture was transferred was transferred to a to a 200LLglass 200 glassreactor reactorand andstirred stirredfor foratatleast least one onehour. hour.TheThe phases phases werewere separated separated andorganic and the the organic layer was layer wastransferred transferredtotoaa100 100L Lreactor reactorandand washed washed with with 2 N(29 2 N HCI HClL),(29 L),10% then then 10% aqueous aqueous sodiumbicarbonate sodium bicarbonate (29(29 L), L), and and the the organic organic layerlayer was concentrated was concentrated under at under vacuum vacuum at a70 70 °C to °C to a volumeof volume of 29 29 L. L. Isopropanol Isopropanol (58 (58 L) L) was added and was added and the the mixture mixture was was concentrated concentrated under under vacuum vacuum

at 70 at °C to 70 °C to aa volume volumeofof2929L. L.Isopropanol Isopropanol (58was (58 L) L)again was again added, added, and theand the mixture mixture was was concentratedtotoa afinal concentrated final volume volumeof of 28 28 L. L. Purified Purified water water (29was (29 L) L) added, was added, and theand the mixture mixture was was heated toto between heated between50-60 50-60 °C with °C with stirring stirring until until complete complete dissolution dissolution was observed. was observed. The The mixture mixture

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wasthen was thencooled cooledtotobetween between 0-100-10 °C stirred °C and and stirred forleast for at at least 14 hours. 14 hours. The resulting The resulting solids solids were were 2023206094 18 Jul 2023

collected by collected by filtration, filtration, washed withpurified washed with purifiedwater water (12(12 L),L), andand dried dried in ainvacuum a vacuum oven oven at at 25 °C 25 °C for at for at least least 12 12 hours. Theisolated hours. The isolatedintermediate intermediate(R)-G-6-a (R)-G-6-a (6962(6962 g)used g) was waswithout used without further further

purification in purification in the the next step. next step.

AlternativeStep Alternative Step 4. 4. Synthesis Synthesis of (R)-G-6-a of (R)-G-6-a

[0515] 2-Methyltetrahydrofuran

[0515] 2-Methyltetrahydrofuran (1300 mL) mL) (1300 was charged to a to was charged a reactor reactor containing containing (R)-G-5-a (R)-G-5-a

(200 g, (200 g, 1.0 1.0 equiv.), equiv.), followed followedbybytrimethylamine trimethylamine (120(120 g, equiv.). g, 1.5 1.5 equiv.). The contents The contents were cooled were cooled to to 5 °C 5 (2 to °C (2 to 88 °C) C) and andmethanesulfonyl methanesulfonyl chloride chloride (109 (109 g, equivalents) g, 1.2 1.2 equivalents) was charged was charged while while maintainingthe maintaining thereaction reactioncontents contents at at no no more more thanthan about about 252-Methyltetrahydrofuran 25 °C. °C. 2-Methyltetrahydrofuran (120 (120 mL)was mL) was used used to to rinse rinse forward forward the the methanesulfonyl methanesulfonyl chloride chloride and theand the reaction reaction wastowarmed was warmed to about 2222°C°Candandstirred about stirreduntil untilthe thereaction reactionwas was complete. complete. Water Water (1600(1600 mL) mL) was was then then slowly slowly addedsuch added suchthat thatthe theinternal internaltemperature temperaturewaswas lessless thanthan about about 40 °C40 °Cthe and andsolution the solution was agitated was agitated

for about for 30minutes. about 30 minutes.Agitation Agitation was was stopped stopped andsolution and the the solution was allowed was allowed to settle. to settle. The The bottom bottom aqueouslayer aqueous layerwas was removed removed andorganic and the the organic layer layer was washed was washed with anHCI with an aqueous aqueous HCl solution solution (about 160 (about 160g gconcentrated concentratedHCIHCl in 664 in 664 g water) g water) at about at about 22Agitation 22 °C. °C. Agitation wasstopped was again again stopped and and the solution the solution was wasallowed allowedto to settle.TheThe settle. bottom bottom aqueous aqueous layer layer was removed was removed and thelayer and the organic organic layer was then was then washed with an washed with an aqueous aqueous sodium sodiumbicarbonate bicarbonate solution solution (about (about 72 72 ggNaHCO3 in 776g NaHCO3 in 776g water) atat about water) about2222°C. °C.Agitation Agitation was was again again stopped stopped andsolution and the the solution was allowed was allowed to settle. to settle. The The bottom aqueous bottom aqueous layer layer was removedand was removed andthe the organic organic layer layer was was then then washed washed with with water water (800 (800 mL, mL,

about 4.0 about 4.0 v/w v/w(R)-G-5-a). (R)-G-5-a). Agitation Agitation was was againagain stopped stopped and and the the solution solution was allowed was allowed to to settle. settle. Thebottom The bottom aqueous aqueous layer layer was was removed. removed. The organic The organic layers layers were were distilled distilled undertovacuum under vacuum to about 3V about pot volume. 3V pot 2-Propanol(1200 volume. 2-Propanol (1200 mL, mL,about about6.0 6.0 v/w v/w(R)-G-5-a) (R)-G-5-a) was wasadded addedand andthe the reaction was reaction wasdistilled distilled to to about about6V6Vpotpotvolume volume twice. twice. Water Water (1000 (1000 mL,5.0 mL, about about 5.0 v/w (R)-G-5-a) v/w (R)-G-5-a)

wasthen was thenadded addedandand thethe solution solution warmed warmed to between to between about about 55 °C to55 °C to65 about about °C . The 65solution °C. The solution wasthen was thencooled cooledtotoabout about 22 22 °C °C (19 (19 to °C) to 25 25 C) and and (R)-G-6-a (R)-G-6-a seeds according seeds (made (made according to this to this methodororfrom method from a previous a previous alternate alternate route route suchsuch as described as described herein) herein) (0.6about (0.6 g, g, about 0.003 0.003 w/w w/w (R)- (R) G-6-a)were G-6-a) wereadded added and and the the solution solution was was cooled cooled to about to about 5 °C 5 °C and and filtered. filtered. The cake The filter filterwas cake was washed with washed with water water (about (about 400 mL, mL, 2.0 2.0 v/w (R)-G-6-a) and v/w (R)-G-6-a) and dried dried to toafford afford(R)-G-6-a. (R)-G-6-a.'H¹HNMR NMR

(400 MHz, (400 MHz, CDC3): CDCl): 7.48 67.48J =(d,7.6J= (d, 7.61H), Hz, Hz,7.33 1H),(t,7.33 J = (t, 8.0J= Hz,8.0 Hz,7.02 1H), 1H), (t,7.02 J = (t, 7.6J= Hz,7.6 Hz, 1H), 1H),

6.91 (d, 6.91 (d, J= 8.0 Hz, J = 8.0 Hz, 1H), 1H),5.21 5.21(d, (d, JJ= 8.0Hz, = 8.0 Hz,1H), 1H),4.34 4.34 (d,(d, J =J = 10.8 10.8 Hz,Hz, 1H), 1H), 4.194.19 (dd,(dd, J = J= 8.0,8.0,

10.8 Hz), 10.8 Hz), 4.01 4.01 (m, 1H), (m,1H), 3.90 3.90(m,(m, 1H),3.87 1H), 3.87 (s, (s, 3H), 3H), 3.553.55 (m, (m,1H), 1H), 3.40 3.40 (dq, (dq, J= 9.8, J = 9.8, 2.22H), 2.2 Hz, Hz, 2H), 3.04 (s, 3.04 (s, 3H), 2.02 (m, 3H), 2.02 1H), (m, 1H), 1.82 1H), 1.82(m,(m,1H), 1.661.66 (m, (m, 2H).2H).

Step 5.5. Synthesis Step Synthesisofof(R)-G-1-a (R)-G-1-a

[0516] IntoInto

[0516] a 100 a 100 L reactorunder L reactor undernitrogen nitrogenwas wascharged chargedN-methylpyrrolidinone N-methylpyrrolidinone(NMP, (NMP, 14 14 L), and L), the reactor and the reactor was wascooled cooledto to0-10 0-10 °C.°C. Lithium Lithium bromide bromide (9189 (9189 g) g) was was added in added three in three

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portions over portions overone onehour hourto tothethereactor reactorallowing allowing the the temperature temperature to return to return to between to between 0-10 0-10 °C °C after after 2023206094 18 Jul 2023

each addition. each addition. The The mixture mixture was was heated heated to tobetween between 55-65 55-65 °C. °C. (R)-G-6-a (6962 g) (R)-G-6-a (6962 g) was was combined combined

with in with in NMP NMP (14 inL)a in72 aL72 (14L) L reactor reactor and stirred and stirred at 30-40 at 30-40 °C until °C until completely completely dissolved. dissolved. This This solution was solution wastransferred transferredtotothe the100 100L L reactor reactor containing containing the the lithium lithium bromide bromide solution, solution, and and the the mixturewas mixture wasstirred stirredatat50-60 50-60°C °C forfor 18 18 hours, hours, taking taking samples samples for analysis for analysis by every by HPLC HPLChour, every hour, until the until the amount amount ofof(R)-G-6-a (R)-G-6-a remaining remaining was was no nothan more more1%.than The 1contents Theofcontents the 100 of L the 100 L reactor were reactor werecooled cooledtoto15-25 15-25 °C °C and and transferred transferred to a to a 200 200 L glass L glass reactor reactor together together with purified with purified

water(70 water (70and L) ethyl and ethyl acetate acetate (70andL),theand (70L), the mixture mixture was for was stirred stirred for at15least at least 15 minutes, minutes, then then the phases the wereseparated. phases were separated.TheThe aqueous aqueous phase phase was extracted was extracted withacetate with ethyl ethyl acetate (35 (35 L) with L) with stirring for stirring for at atleast least15 15minutes. Thecombined minutes. The combined organic organic phases phases were washed were washed with twowith two portions portions of of brine (35 brine (35 LLeach) each)and andtwotwo portions portions of purified of purified water water (35 (35 L each), L each), then then concentrated concentrated to dryness to dryness

undervacuum under vacuum at 40-50 at 40-50 °C, °C, affording affording (R)-G-1-a (R)-G-1-a (6691 (6691 g, g, 92%asyield) 92% yield) as an oil. an oil. Alternative Synthesis Alternative Synthesis of of (R)-G-1-a (R)-G-1-a

[0517] 1-Methyl-2-pyrolidinone

[0517] 1-Methyl-2-pyrolidinone (NMP) (NMP) (148 (148 g, about g, about 2.4 v/w 2.4 v/w was was charged charged to atoreactor, a reactor, agitated, and agitated, adjustedtotoabout and adjusted about5 5°C. °C.Lithium Lithium bromide bromide (26.4(26.4 g, about g, about 0.44(R)-G-6-a, 0.44 w/w w/w (R)-G-6-a, 1.67 1.67 equiv.) was equiv.) wasthen thenadded added batch-wise batch-wise to the to the reactor reactor and and agitated agitated for about for about 30 minutes. 30 minutes. Once Once the the temperaturereached temperature reached about about 5 °C, 5 °C, the the nextnext charge charge of lithium of lithium bromide bromide (26.4 (26.4 g, g, 0.44 about aboutw/w0.44 w/w (R)-G-6-a,1.67 (R)-G-6-a, 1.67equiv.) equiv.)waswas performed. performed. Once Once the reaction the reaction cooled cooled back back down to down about 5to°C, about a 5 °C, a third and third final charge and final charge ofoflithium lithiumbromide bromide (26.4 (26.4 g, about g, about 0.440.44 w/w w/w (R)-G-6-a, (R)-G-6-a, 1.67 equiv.) 1.67 equiv.) was was performed.Additional performed. Additional NMPNMP (37.1 (37.1 g, about g, about 0.6(R)-G-6-a) 0.6 v/w v/w (R)-G-6-a) was addedwas and added and the temperature the temperature

wasadjusted was adjustedtotoabout about5555°C.°C. In In a separate a separate reactor reactor waswas charged charged (R)-G-6-a (R)-G-6-a (60.0 (60.0 g, g, 1.0 about about 1.0 equivalent) followed equivalent) followedbyby NMPNMP (80.3(80.3 g, about g, about 2.3(R)-G-6-a), 2.3 v/w v/w (R)-G-6-a), which which was then was then heated to heated to about 3030°C°Ctotoabout about about3838 °C °C with with agitation agitation until until all all solids solids were were dissolved. dissolved. The The NMP solution NMP solution of of (R)-G-6-awaswas (R)-G-6-a charged charged to the to the about about 55 °C55NMP °Clithium NMP lithium bromideTheslurry. bromide slurry. The solution (R)-G-6-a (R)-G-6-a solution wasrinsed was rinsedforward forward with with NMPNMP (43.3 (43.3 g, about g, about 0.7(R)-G-6-a) 0.7 v/w v/w (R)-G-6-a) and then and thenatstirred stirred about at 55 about °C. 55 °C. Oncecomplete, Once complete,thethe potpot temperature temperature was adjusted was adjusted to about to about 22 °C,22 and°C, and(300.1 water waterg,(300.1 about g, 5 about 5 v/w(R)-G-6-a) v/w (R)-G-6-a)waswas charged charged slowly slowly to quench to quench the reaction the reaction such such that thethat pot the pot temperature temperature remains remains no more no morethan thanabout about 30 30 °C.°C. Ethyl Ethyl acetate acetate (271.0 (271.0 g, about g, about 5 v/w 5(R)-G-6-a) v/w (R)-G-6-a) was and was charged charged the and the solution was solution wasagitated. agitated.The Thelayers layerswere were allowed allowed to separate to separate andaqueous and the the aqueous layer layer was was removed removed

and set and set aside. aside. To To this this aqueous aqueouslayer layerwaswas charged charged ethyl ethyl acetate acetate (271.1 (271.1 g, about g, about 5 v/w 5(R)-G-6-a) v/w (R)-G-6-a) and the and the solution solutionwas wasagitated. agitated.The The layers layers were were thenthen allowed allowed to separate, to separate, andaqueous and the the aqueous layer layer wasdisposed was disposedof.of.TheThe ethyl ethyl acetate acetate organic organic layers layers were were combined combined and and brine wasbrine addedwas added

[(water, [(water, 291.0 g,g, 44 about.8 291.0 about.85 v/wv/w (R)-G-6-a), (R)-G-6-a), (sodium (sodium chloride, chloride, 29.1 g,29.1 g, 0.485 about aboutw/w 0.485 w/w (R)-G-6-a)], (R)-G-6-a)], the the temperaturewas temperature was adjusted adjusted to to about about 22 °C, 22 °C, and mixture and the the mixture agitated. agitated. The layers The layers were were then then separated. The separated. Theorganic organiclayer layerwaswas washed washed with with water water (300.0(300.0 g, 5about g, about 5 v/w (R)-G-6-a) v/w (R)-G-6-a) and the and the

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mixtureagitated. mixture agitated. The Thewater water layer layer waswas discarded, discarded, and and another another final final waterwater (300.0(300.0 g, about g, about 5 v/w 5 v/w 2023206094 18 Jul 2023

(R)-G-6-a)wash (R)-G-6-a) wash waswas performed. performed. The organic The organic layer layer was was distilled distilled to 3Vabout to about (pot 3V (pot with volume) volume) with maxjacket max jackettemperature temperature at about at about 45 °C. 45 °C. OnceOnce at about at about 3V, acetonitrile 3V, acetonitrile (ACN) (ACN) (376.0 (376.0 g, about g, 8 about 8 v/w(R)-G-6-a) v/w (R)-G-6-a)waswas charged charged to reactor to the the reactor and contents and contents distilled distilled down down to 3about to about 3 V (pot V (pot volume)with volume) withmaxmax jacket jacket temperature temperature at about 45 °C.45NMP at about °C.(185.0 NMPg,(185.0 about g, 5.5about 5.5 v/w (R)-G-6-a) v/w (R)-G-6-a)

wasthen was thenadded, added,andand thethe contents contents distilled distilled to to about about 3.33.3 V (pot V (pot volume) volume) withjacket with max max jacket temperatureatatabout temperature about9090 °C.°C. Once Once distillation distillation waswas complete, complete, a NMPa stock NMPsolution stock solution of (R)-G-1-a of (R)-G-1-a

was achieved. was achieved. Example35. Example 35.Synthesis Synthesis ofof Compound Compound 1 - Route 1- Route A A

CO 2 Et COEt CO 2 Et COEt CO 2EtBr COEt Br O O O o S NH S ON NH S NH S S 2 NH NH2 NH IZ IZ N

" O N H O H H H 0 O 0 O o OH Br Br N N Br N OH Br S S N- N O0 o S N'JO 0 O H O H S N H O H G-2-a G-2-a

0 o N OBn OBn Br Br N O S O N O O O Br BrN OBn Br S H o O .1%0N N O O O H

G-2-b G-2-b G-3-b G-3-b

o o 0 o N N OBn OBn N N N OH OH N N N S o O S o O N O N 0 0 a, C, - I0. - O O N ~ N0 o o o o

G-4-b G-4-b Compound 11 Compound Step 1. Step 1. Synthesis Synthesis of of Ethyl Ethyl 4-methyl-2-[3-(1-methyl-1-tert-butoxycarbonylethyl)ureido]-3 4-methyl-2-[3-(1-methyl-1-tert-butoxycarbonylethyl)ureido]-3-

thenoate thenoate

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[0518] IntoInto

[0518] a 300 a 300 L reactor undernitrogen L reactorunder addeddichloromethane wasadded nitrogenwas (136.47L),L),followed dichloromethane(136.47 followed 2023206094 18 Jul 2023

by ethyl by ethyl 2-amino-4-methylthiophene-3-carboxylate 2-amino-4-methylthiophene-3-carboxylate (12.91 (12.91 kg, 1.0 kg, 1.0 15-25 eq) at eq) at°C.15-25 °C. Carbonyldiimidazole Carbonyldiimidazole (12.66 (12.66 kg, eq) kg, 1.1 1.1 was eq) added, was added, while while maintaining maintaining the temperature the temperature between between 15-25 °C. 15-25 °C. The The mixture mixture was was stirred stirred at that at that temperature, temperature, taking taking samples samples and quenching and quenching with with methanolandand methanol analyzing analyzing by IPC by IPC untiluntil the starting the starting material material was determined was determined to be present to be present at 2.0% at 2.0% or less or less (typically (typically 12 12 hours). Oncethis hours). Once thiscriterion criterionwas was met, met, trimethylamine trimethylamine (7.80(7.80 kg,eq) kg, 1.1 1.1was eq) was addeddropwise added dropwiseat at a temperature a temperature below below 25tert-Butyl 25 °C. °C. tert-Butyl 2-amino-2-methylpropionate 2-amino-2-methylpropionate

hydrochloride(14.98 hydrochloride (14.98kg,kg, 1.11.1 eq)eq) waswas added added in portions, in portions, maintaining maintaining the temperature the temperature below 25below 25 °C. The °C. Thereaction reactionwaswas stirred stirred forfor 5 hours 5 hours at at a temperature a temperature between between 15-25 15-25 °C, taking °C, taking samples, samples,

quenchingwith quenching with methanol methanol and and analyzing analyzing with with IPC IPCthe until until the intermediate intermediate isocyanate isocyanate was was determinedtotobebepresent determined present at at 3.0% 3.0% or less. or less. Once Once this this criterion criterion was was met, met, purified purified water water (52.52(52.52 L) L) wascharged was chargedinto intothethereactor, reactor,andand thethe mixture mixture was was stirred stirred for for 30 minutes, 30 minutes, then then allowed allowed to to stand stand for 15 for 15 minutes. minutes.TheThe phases phases werewere allowed allowed to separate to separate andorganic and the the organic layer layer was was collected collected and and washedwith washed with water water (two (two portions portions of 52.50 of 52.50 L). organic L). The The organic layer layer was was concentrated concentrated under under vacuum vacuum at aa temperature at below temperature below 40 40 °C °C until until no no more more than than four four volumes volumes of solvent of solvent remained. remained. MTBE MTBE (39.27 L,L, 33 volumes) (39.27 volumes)waswas charged charged into into the reactor, the reactor, and mixture and the the mixture was concentrated was again again concentrated under under vacuum vacuum at at a temperature a temperature below below 40 °C40 °C until until no than no more morefour thanvolumes four volumes ofremained. of solvent solvent remained. Again,MTBE Again, MTBE (39.27 (39.27 L, 3 L, 3 volumes) volumes) was charged was charged into the into the reactor, reactor, and the was and the mixture mixture again was again concentratedunder concentrated under vacuum vacuum at a at a temperature temperature below below 40 °Cnountil 40 °C until more no more than fourthan fourofvolumes volumes of solvent remained. solvent remained.Petroleum Petroleum etherether (40.00 (40.00 L, 3 L, 3 volumes) volumes) was charged was charged into the into the reactor, reactor, and the and the mixturewas mixture wasstirred stirredfor forfive fivehours hoursbetween between 15-25 15-25 °C. mixture °C. The The mixture was centrifuged, was centrifuged, filtered,filtered, and and the resulting the resulting cake cake was waswashed washedwithwith petroleum petroleum ether ether (13.11(13.11 L, 1 volume), L, 1 volume), thenindried then dried in a a vacuum vacuum ovenatat 35-45 oven 35-45°C°Cforforsixsixhours, hours,resulting resultingin in23.38 23.38 kg kg of the of the desired desired product product (90.5% (90.5% yield,yield, 98.0% 98.0%

yield) as yield) as an off-white solid. an off-white solid.

[0519]

[0519] In embodiments, someembodiments, In some heptanes heptanes is used is used in place in place of petroleum of petroleum ether. ether. Step 2. Step 2. Synthesis Synthesis of ofEthyl Ethyl 5-bromo-4-methyl-2-[3-(1-methyl-1-tert 5-bromo-4-methyl-2-|3-(1-methyl-1-tert-

butoxycarbonylethyl)ureido]-3-thenoate butoxycarbonylethyl)ureido|-3-thenoate

[0520] IntoInto

[0520] a 500 a 500 L reactorunder L reactor undernitrogen nitrogenwas wascharged chargedDMF DMF (279.47 (279.47 L) L) followed followed by by ethyl ethyl

4-methyl-2-[3-(1-methyl--tert-butoxycarbonylethyl)ureido]-3-thenoate 4-methyl-2-[3-(1-methyl-1-tert-butoxycarbonylethyl)ureido]-3-thenoate (23.38 (23.38 kg, kg, 1.0 1.0 eq.). Theeq.). The mixturewas mixture wascooled cooled to to -10-10 to to 0 °C, 0 °C, andand N-bromosuccinimide N-bromosuccinimide (11.22 (11.22 kg, kg, 1.0 1.0 eq.) was eq.) addedwas added batchwise,maintaining batchwise, maintainingthethe temperature temperature below below 0 °C. 0The °C.mixture The mixture wasatstirred was stirred at that temperature that temperature

for one for hour, sampling one hour, samplingandand assaying assaying by IPC by IPC each each half half an an until hour hour until nothan no more more than 2.0% of 2.0% the of the starting material starting remained.Once material remained. Once the the reaction reaction was was deemed deemed complete complete accordingaccording to this criterion, to this criterion,

the mixture the waspoured mixture was poured into into purified purified water water (1000 (1000 L, 42L,volumes) 42 volumes) slowly,slowly, and stirred and stirred for two for two hours. The hours. Themixture mixture waswas centrifuged, centrifuged, filtered, filtered, and and the the collected collected solids solids were were washed washed with with water water

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(48.00 L,L, 22 volumes), (48.00 volumes),then then dried dried forfor 12 12 hours hours at 35-45 at 35-45 °Ca in °C in a vacuum vacuum oven. oven. The The (26.20 product product (26.20 2023206094 18 Jul 2023

kg, 92.39% kg, 92.39%yield, yield,98.8% 98.8% purity) purity) was was isolated isolated asoff-white as an an off-white solid, solid, andahad and had a water water contentcontent less less than 0.07% than 0.07%byby Karl Karl Fischer Fischer titration. titration.

In some

[0521] In some

[0521] aboutabout embodiments, embodiments, 15 volumes 15 volumes of purified of purified water water be be can can used used in in placeofof4242 place

volumes. volumes.

Step 3.3. Synthesis Step Synthesisofoftert-Butyl tert-Butyl2-(2-bromo-3-methyl-4,6-dioxo-1-thia-5,7-diaza-5,7- 2-(2-bromo-3-methyl-4,6-dioxo-1-thia-5,7-diaza-5,7 dihydroinden-5-yl)-2-methylpropionate(G-2-a) dihydroinden-5-yl)-2-methylpropionate (G-2-a)

[0522] IntoInto

[0522] a 1000 a 1000 L reactor L reactor undernitrogen under nitrogenwas wascharged charged1,4-dioxane 1,4-dioxane(393 (393L,L,30 30volumes, volumes, 0.03%water 0.03% water by by Karl Karl Fischer), Fischer), followed followed by ethyl by ethyl 5-bromo-4-methyl-2-[3-(i-methyl-1-tert 5-bromo-4-methyl-2-[3-(1-methyl-1-tert-

butoxycarbonylethyl)ureido]-3-thenoate butoxycarbonylethyl)ureido]-3-thenoate (13.09 (13.09 kg,eq.). kg, 1.0 1.0 eq.). Potassium Potassium tert-butoxide tert-butoxide (16.27 (16.27 kg, kg, 5.0 eq.) 5.0 eq.) was addedininbatches. was added batches.TheThe mixture mixture was heated was heated to between to between 40-50 40-50 °C, °C, andatstirred and stirred that at that temperaturefor temperature forapproximately approximately 1 hour, 1 hour, sampling sampling and assaying and assaying by HPLCby HPLC every every 30 30 minutes minutes until until the content the content ofofthe the starting starting material material was wasdetermined determined to be to be no more no more than than 2.0%. 2.0%. Once Once the the reaction reaction

wasdetermined was determinedto to be be complete, complete, the the mixture mixture was cooled was cooled to between to between 20-30 20-30 °C, °C, poured and then and then poured into aa solution into of ammonium solution of ammonium chloride chloride (327.50 (327.50 kg) inkg) in water water (1310.00 (1310.00 kg, 100 kg, 100 volumes) volumes) that had that had beencooled been cooledtotobetween between 0-10 0-10 °C. °C. The quenched The quenched mixture mixture wasfor was stirred stirred for two two hours at ahours at a temperaturebetween temperature between0-100-10 °C, °C, whereupon whereupon the precipitate the precipitate was collected was collected by centrifugation by centrifugation and and filtration. The filtration. resulting solid The resulting solid was waswashed washed with with water water (52.00 (52.00 L, 4 L, 4 volumes), volumes), then in then dried dried a in a vacuum vacuum oven oven held held at 35-45 at 35-45 °C 12 °C for forhours 12 hours whereupon whereupon Karl analysis Karl Fischer Fischer analysis indicated indicated that the that the water content water contentwas wasless lessthan than 1.0%. 1.0%. The The solidsolid material material was collected, was collected, amounting amounting to 8.89 to 8.89 kg of thekg of the product(75.68% product (75.68% yield, yield, 97.1% 97.1% purity) purity) asoff-white as an an off-white solid. solid.

Alternative process Alternative process to to G-2-a G-2-a

[0523] To ethyl

[0523] To ethyl 5-bromo-4-methyl-2-[3-(1-methyl--tert-butoxycarbonylethyl)ureido]-3 5-bromo-4-methyl-2-[3-(1-methyl-1-tert-butoxycarbonylethyl)ureido]-3-

thenoate(0.65 thenoate (0.65kg, kg,1.0 1.0eq.) eq.)was wascharged charged 1,4-dioxane 1,4-dioxane (20.3(20.3 kg,v/w). kg, 30 30 v/w). The resulting The resulting slurry slurry is is then analyzed then analyzedbybyKFKF and and water water is added is added such such thatis KF that KF is between between about about 0.1% and 0.1% about and about 0.4%. Potassium 0.4%. Potassium tert-butoxide tert-butoxide (0.85 (0.85 kg,eq.) kg, 5.0 5.0 was eq.)then wasadded then and added and 1,4-dioxane 1,4-dioxane (0.52 kg, (0.52 0.8 kg, 0.8 w/w) was w/w) wasadded addedtoto wash washdown downthe thehopper. hopper. The Themixture mixturewas washeated heatedtotoabout about47 47°C °Cuntil until deemed deemed

complete,and complete, andthen thencooled cooled to to between between aboutabout 10 °C 10 and°C and 20 about about 20 which °C, at °C, atpoint which pointacid acetic acetic acid (0.44 kg, (0.44 kg, 55 eq.) eq.) is is slowly addedsuch slowly added such thatthethetemperature that temperature remains remains within within this range. this range. WaterWater (1.95 (1.95 kg, 33 v/wt) kg, v/wt) is is added andthe added and theaqueous aqueous layer layer cut. cut. While While keeping keeping thetemperature the pot pot temperature at at below below about 4040°C, about °C,the thereaction reactionisisthen thenconcentrated concentratedto to about about I1V, 11V, then then waterwater (12.8(12.8 kg, w/w) kg, 19.7 19.7 isw/w) is addedatat35°C added 35°Cover over 3 hours. 3 hours. TheThe isolation isolation mixture mixture is cooled is cooled to over to 15°C 15°C2over hours2 and hours anda after after a further stirring further stirring (>1 (>1 hr) hr) the the quenched mixture quenched mixture waswas filtered. filtered. The The resulting resulting cake cake was washed was washed with with 1,4-Dioxane/ /demineralized 1,4-Dioxane demineralized water water (1/2(1 (w/w) /2 (w/w) (2,62 (w/w)), 2,62 w/w)), followedfollowed bywith by washing washing with demineralizedwater demineralized water (0,5 (0,5 w/w). w/w). The The wet product wet product is dried is dried under under vacuumvacuum at 35 °C-at45 35°C. °C- 45 °C.

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Step 4. Step 4. Synthesis Synthesis of of2-(2-Bromo-3-methyl-4,6-dioxo-1-thia-5,7-diaza-5,7-dihydroinden-5 2-(2-Bromo-3-methyl-4,6-dioxo-1-thia-5,7-diaza-5,7-dihydroinden-5- 2023206094 18 Jul 2023

yl)-2-methylpropionic acid yl)-2-methylpropionic acid

[0524] IntoInto

[0524] a 300 a 300 L reactor L reactor under under nitrogenwas nitrogen wascharged chargeddichloromethane (176.70L,L,1010 dichloromethane(176.70 volumes),followed volumes), followed by by intermediate intermediate G-2-a G-2-a (17.74(17.74 kg,eq.). kg, 1.0 1.0 Trifluoroacetic eq.). Trifluoroacetic acidL,(32.4 acid (32.4 2 L, 2 volumes)was volumes) was added added dropwise dropwise at a temperature at a temperature between between 15-25 15-25 °C, °C, reaction and the and the was reaction was stirred at stirred at this temperature this forthree temperature for threehours, hours,sampling sampling periodically periodically for for analysis analysis by IPC by IPC untiluntil the amount the amount of of starting material starting remainingwaswas material remaining no no more more than than 2.0%.2.0%. The mixture The mixture was then was then cooled to cooled between to 0-between 0 10 °C, 10 °C, and andwater water(182.41 (182.41L, L, 10 10 volumes) volumes) was added was added dropwise, dropwise, maintaining maintaining the temperature the temperature

between0-10 between 0-10 °C.°C. The The reaction reaction mixture mixture was stirred was stirred forhours for two two at hours this at this temperature, temperature, and thenand then the solid the solid formed was formed was collected collected by by centrifugation centrifugation and and filtration. filtration. The The solidsolid was washed was washed with with dichloromethane dichloromethane (2.3 (2.3 volumes), volumes), and water and water (5 volumes), (5 volumes), thenindried then dried in a vacuum a vacuum oven heldoven held at 35- at 35 45 °C 45 °Cfor for1212hours, hours,whereupon whereuponKarl Karl Fischer Fischer analysis analysis indicated indicated thatwater that the the water contentcontent was was less less than 0.5%. than 0.5%.TheThe solid solid material material was was collected, collected, amounting amounting to 13.2tokg13.2 kg of of the the product product (86.7% yield, (86.7% yield, 98.1%purity) 98.1% purity)asasananoff-white off-white solid. solid.

Step 5. Step 5. Synthesis Synthesis of of Benzyl 2-(2-bromo-3-methyl-4,6-dioxo-1-thia-5,7-diaza-5,7 Benzyl2-(2-bromo-3-methyl-4,6-dioxo-1-thia-5,7-diaza-5,7

dihydroinden-5-yl)-2-methylpropionate(G-2-b) dihydroinden-5-yl)-2-methylpropionate (G-2-b)

[0525] IntoInto

[0525] a 300 a 300 L reactorunder L reactor under nitrogenwas nitrogen wascharged chargeddichloromethane dichloromethane(116.7 (116.7L,L,1010 volumes),followed volumes), followed by by 2-(2-Bromo-3-methyl-4,6-dioxo-1-thia-5,7-diaza-5,7-dihydroinden-5-yl) 2-(2-Bromo-3-methyl-4,6-dioxo-l-thia-5,7-diaza-5,7-dihydroinden-5-yl)-

2-methylpropionic 2-methylpropionic acid acid (11.50 (11.50 kg, kg, 1.0 1.0 eq.). eq.). Carbonyldiimidazole Carbonyldiimidazole (CDI, (CDI, 6.51 kg, 6.51 kg, 1.2 1.2 eq.) was eq.) was addedbatchwise added batchwiseto to thethe reactor,maintaining reactor, maintaining the the temperature temperature ofmixture of the the mixture below below 25 25 °C. The °C. The reaction mixture reaction mixturewas was stirredforforthree stirred threehours hours at at a a temperature temperature between between 20-3020-30 °C, sampling °C, sampling hourly, hourly, quenchingwith quenching with methanol, methanol, for for analysis analysis by until by IPC IPC until the amount the amount of starting of starting material material remaining remaining

wasdetermined was determinedto to be be no no more more than than 3.0%.3.0%. Benzyl Benzyl alcohol alcohol (4.64 (4.64 kg, kg, 1.3 1.3 eq.) was eq.) then was then charged charged slowlyinto slowly into the the reactor, reactor, keeping keepingthe thetemperature temperature below below 25 The 25 °C. °C.mixture The mixture was for was stirred stirred two for two hours atat this hours this temperature, sampling temperature, sampling hourly, hourly, quenching quenching with with methanol, methanol, for analysis for analysis by IPC by IPC until until the amount the amountofofthe theintermediate intermediate waswas no more no more than 2.0%. than 2.0%. Water Water (3 (3 volumes) volumes) was added was added to the to the mixture, which mixture, whichwaswas stirred stirred forfor 30 30 minutes, minutes, whereupon whereupon the phases the phases were allowed were allowed to separate, to separate, and and the organic the organic phase phasewas was collected, collected, washed washed firstfirst withwith 1%(3HCl 1% HCI (3 volumes), volumes), then 2% then 2% sodium sodium bicarbonate(3(3volumes), bicarbonate volumes),andand finally finally water water (3 volumes). (3 volumes). The organic The organic phase phase was was concentrated concentrated

undervacuum under vacuum at temperature at a a temperature below below 50 °C 50 °C the until untilremaining the remaining residue residue was not was more not thanmore 4 than 4 volumes. MTBE volumes. MTBE(4 (4 volumes) volumes) waswas added added to the to the reactor, and reactor, andthe the mixture mixture was was again again concentrated concentrated under vacuum under below5050°C°Cuntil vacuum below until the the remaining remaining residue residue was was not not more more than than 44volumes. volumes. MTBE MTBE (4(4

volumes)was volumes) was again again added added to reactor to the the reactor and mixture and the the mixture concentrated concentrated underuntil under vacuum vacuum the until the remaining residue remaining residue was was not not more more than than 44 volumes. One volume volumes. One volumeofofMTBE MTBEwaswas added added to the to the

reactor, and reactor, the mixture and the mixturewas was stirredforforover stirred over fivehours five hours at at a temperature a temperature between between 5-15The 5-15 °C. °C. The

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solid formed solid formedwas was centrifuged centrifuged and and collected collected by filtration. by filtration. IntoInto a 300 a 300 L reactor L reactor was charged was charged 2023206094 18 Jul 2023

purified water purified water(86.25 (86.25L,L,7.5 7.5volumes) volumes)and and acetonitrile acetonitrile (28.75 (28.75 L, volumes), L, 2.5 2.5 volumes), followed followed by the by the solid isolated solid isolated in in the the previous step. The previous step. Themixture mixture waswas stirred stirred for for 2-32-3 hours hours at a at a temperature temperature

between15-25 between 15-25 °C,°C, then then centrifuged, centrifuged, and and the resulting the resulting solidsolid collected collected by filtration. by filtration. The solid The solid was was dried in dried in aa vacuum oven vacuum oven for for 12 hours 12 hours at aattemperature a temperature between between 35-45 35-45 °C. The °C. The crude crude product product (9.83 kg, (9.83 kg, 67.8% 67.8%yield, yield,97.7% 97.7% purity) purity) was was isolated isolated asoff-white as an an off-white solid. solid. This This product, product, plus plus that that producedinina aseparate produced separaterunrun (1.55kg)kg) (1.55 were were purified purified together together by stirring by stirring forhours for 16 16 hours in a in a mixture mixture

of acetonitrile of acetonitrile (20 L), and (20L), andpurified purifiedwater water(60(60 L) L) in in a 200 a 200 L drum L drum at 25at°C. 25 The °C. solids The solids were were centrifuged, collected centrifuged, collectedbybyfiltration, filtration, and and dried driedinin aa vacuum vacuum oven oven at 35-45 at 35-45 °C 12forhours. °C for 12 hours. The The total overall total overall yield yield of of G-2-b was11.18 G-2-b was 11.18 kg kg (67.2% (67.2% yield, yield, 98.9%98.9% purity) purity) as an as an off-white off-white solid. solid. Step 6. Step 6. Synthesis Synthesis of ofBenzyl Benzyl 2-{7-[(R)-2-(o-methoxyphenyl)-2-(tetrahydro-2H-pyran-4 2-{7-[(R)-2-(o-methoxyphenyl)-2-(tetrahydro-2H-pyran-4-

yloxy)ethyl]-2-bromo-3-methyl-4,6-dioxo-1-thia-5,7-diaza-5,7-dihydroinden-5-yl}-2 yloxy)ethyl|-2-bromo-3-methyl-4,6-dioxo-1-thia-5,7-diaza-5,7-dihydroinden-5-yl}-2-

methylpropionate(G-3-b) methylpropionate (G-3-b) Cesium

[0526] Cesium

[0526] carbonate carbonate (3369 (3369 g) was g) was dried in ainvacuum dried ovenoven a vacuum 60 60 for for hours at at hours 50-60°C.°C. 50-60

Into aa 100 Into 100 LLglass glassreactor reactorunder undernitrogen nitrogen waswas added added the dried the dried cesium cesium carbonate carbonate (3340 (3340 g) g) in one in one portion, alongwith portion, along with9.2 9.2L LofofNMP. NMP.Into Into a 72 aL 72 L glass glass reactor reactor was charged was charged NMP (15NMP (15 L), (R)-G-1 L), (R)-G-1-

a (3179 a (3179g), g), and andG-2-b G-2-b (3054 (3054 g), g), and and the the mixture mixture was stirred was stirred untiluntil complete complete dissolution dissolution was was observed.TheThe observed. solution solution in the in the 72 72 L reactor L reactor was was transferred transferred to 100 to the the L100 L reactor, reactor, using using additional additional

NMP (6.1L) L) NMP (6.1 to to rinse rinse thethe residual residual contents contents of the of the 72reactor 72 L L reactor intointo the the 100 100 L reactor. L reactor. The The

mixtureininthe mixture the100 100L Lreactor reactorwaswas then then heated heated to 100 to 100 °C, stirred °C, and and stirred at that at that temperature temperature for atfor at least 6060hours, least hours,after which after thethe which amount of of amount G-2-b remaining G-2-b was remaining was10.6% 10.6%bybyHPLC. The HPLC. The

temperaturewas temperature was decreased decreased to between to between 45-55 45-55 °C and °C and purified purified waterwas(23added, water (23L) L) was and added, the and the entire mixture entire transferredtotoa a200 mixture transferred 200L Lglass glassreactor. reactor.Additional Additional purified purified water water (10andL),methyl (10L), and methyl tert-butyl ether tert-butyl (MTBE, ether (MTBE, 31 31 L) L) werewere added, added, andmixture and the the mixture was stirred was stirred for 15 for 15 minutes. minutes. The The phases wereseparated, phases were separated, andand thethe organic organic phase phase was washed was washed with purified with purified water water (31 (31 L). The L). The

aqueousphase aqueous phasewaswas returned returned to the to the reactor, reactor, and and washed washed with(31 with MTBE MTBE (31stirred L), and L), andforstirred 15 for 15 minutes.The minutes. The combined combined organic organic layerslayers were washed were washed with with brine brine (two (two of portions portions of 15 L) and 15 L) and transferred to transferred to aa 100 100 LLreactor. reactor. The The organic organic mixture mixture was concentrated was concentrated under at under vacuum vacuum at 70 °C to 70 °C to aa volume volume ofof 1515 L. L. Ethanol Ethanol (31 (31 L) added L) was was added and theand the mixture mixture was concentrated was concentrated under under vacuum at vacuum at 70 °C 70 °Ctotoaa volume volumeof of 21 21 L, L, andand the the ethanol ethanol addition addition and concentration and concentration was repeated was repeated one moreone more times. The times. Themixture mixture waswas heated heated to between to between 70-80 70-80 °C and °C and stirred stirred until complete until complete dissolution dissolution was was observed.TheThe observed. temperature temperature was decreased was decreased to between to between 45-55 °C45-55 °C over over four four hours, andhours, and held at held that at that temperatureforforfive temperature fivehours. hours.TheThe temperature temperature was decreased was then then decreased to between to between 15-25 °C 15-25 over at°C over at least three least three hours, and held hours, and held atat that that temperature temperatureforforthree threehours. hours.TheThe solids solids formed formed were were vacuumvacuum

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filtered, and filtered, and rinsed rinsed with ethanol(6.1 with ethanol (6.1 L). L). The Theresulting resulting solids solids were were dried dried in ainvacuum a vacuum oven oven at at 2023206094 18 Jul 2023

between35-45 between 35-45 °C °C for for 28 28 hours, hours, affording affording G-3-bG-3-b (2993 (2993 g, 64% g, 64% yield). yield). Step 7.7. Synthesis Step SynthesisofofG-4-b G-4-b

[0527] IntoInto

[0527] a 72 a 72 L glassreactor L glass reactorunder undernitrogen nitrogen with with stirring stirring were werecharged chargedTHF THF (37 (37 L) andand

oxazole(918 oxazole (918g), g),and andthethetemperature temperature was was decreased decreased to between to between -80 and-80 -60 and °C. -60 °C. 2.5 2.5 Molar Molar n-butyllithiumininhexanes n-butyllithium hexanes (3.98 (3.98 kg,kg, stored stored at room at room temperature) temperature) was to was added added to the reactor, the reactor,

maintainingthe maintaining thetemperature temperature of the of the reaction reaction below below -60 The -60 °C. °C. mixture The mixture was at was stirred stirred this at this temperatureforfor9090minutes. temperature minutes. ZincZinc (II)(II) chloride chloride (5059 (5059 g) added g) was was added in portions, in eight eight portions, maintaining maintaining

the temperature the temperature ofof themixture the mixture below below -60 -60 °C, °C, and mixture and the the mixture was stirred was stirred at thatattemperature that temperature for for one hour one hourbefore beforewarming warming to 10-20 to 10-20 °C by°C by removing removing the cooling the cooling bath. Thebath. The ofcontents contents the 72 Lof the 72 L reactor were reactor transferredtotoa a100 were transferred 100L L glassreactor glass reactor under under nitrogen, nitrogen, using using THF THF (4145 (4145 mL) to mL) rinseto rinse the residue the fromthe residue from the7272L Lreactor reactorinto intothethe100100 L reactor. L reactor. The The mixture mixture was stirred, was stirred, and and the the temperaturewas temperature was adjusted adjusted to to between between 10-2010-20 °C. Intermediate °C. Intermediate G-4-b G-4-b (4192 g, (4192 g, was 1.0 eq.) 1.0 added eq.) was added to the to thereactor reactorfollowed bybyPd(PPh3)4(357 followed Pd(PPh) (357 g), and and the the temperature temperature waswas adjusted adjusted totobetween between55-65 55-65 °C, and °C, andthe themixture mixturewaswas stirred stirred at at thattemperature that temperature for for 12 hours, 12 hours, whereupon whereupon the amount the amount of G-4- of G-4 b remaining b remaining was determined by was determined by HPLC HPLCtotobebenonomore morethan than0.07%. 0.07%.TheThe temperature temperature was was

decreasedtotobetween decreased between 15-25 15-25 °C, °C, and and the mixture the mixture was transferred was transferred to La reactor to a 200 200 L reactor togethertogether with with methyltert-butyl methyl tert-butylether ether(MTBE, (MTBE, 41and 41 L) L) purified and purified waterwater (21TheL).mixture (21 L). The mixture wasfor was stirred stirred 18 for 18 minutes,and minutes, andthe thephases phases were were separated. separated. The organic The organic phase phase was stirred was stirred with with MTBE (41MTBE L) and (41 L) and saturated ammonium saturated ammonium chloride chloride (41the (41 L), L),phases the phases separated, separated, and theand the organic organic phaseagain phase washed washed again with saturated with saturatedammonium ammonium chloride chloride (21followed (21 L), L), followed by (21 by 2N HCI 2N HCl (21twice L), and L), and withtwice with purified purified water(21 water (21 LLeach). each).TheThe organic organic layer layer was was transferred transferred to a L100 to a 100 L reactor reactor and concentrated and concentrated under under vacuumatat 70 vacuum 70 °C °C to to aa volume of 41 volume of 41 L. L. The The mixture mixture was cooled to was cooled to between 15-25 °C, between 15-25 °C, and and

transferred to transferred to aa 75 75 LL reactor reactorand andtreated treatedwith withactivated activatedcharcoal charcoal (Darco (Darco G 829 G 60, 60, g), 829and g), stirred and stirred for at for at least least 15 15 hours. Themixture hours. The mixturewaswas filtered filtered through through diatomaceous diatomaceous earth (Celite, earth (Celite, 2520 2520 g) g) slurried in slurried in MTBE MTBE (13(13 L), L), rinsing rinsing the the reactor reactor withwith MTBEMTBE (21 L).(21 The L). The filtrate filtrate was concentrated was concentrated

undervacuum under vacuum at 70 at 70 °C atovolume °C to a volume of 29of L,29 L, twice then then twice diluteddiluted with ethanol with ethanol (41 L), (41 and L), and concentratedtotoa avolume concentrated volume of 29 of 29 L. The L. The temperature temperature was increased was increased to 79 °Ctowhereupon 79 °C whereupon complete complete dissolution was dissolution wasobserved. observed.The The temperature temperature waslowered was then then lowered to between to between 45-55five 45-55 °C over °C over five hours, and hours, andheld heldatatthat that temperature temperatureforfornine ninehours. hours. The The temperature temperature was lowered was lowered to between to between 15- 15 25 °C 25 °Cover overatatleast least 33 hours, hours, and andthe thesolid solidformed formedwaswas collected collected by filtration, by filtration, using using two two portions portions

of ethanol of (4150mLmL ethanol (4150 each) each) to rinse to rinse thethe contents contents of the of the reactor reactor intointo the the filter filter andand wash wash the the filter filter

cake. The cake. Thecollected collected solids solids were were dried dried in ainvacuum a vacuum oven oven at at 45 45 °C for°C 18 for 18 hours, hours, affording affording crude crude G-4-b(3463 G-4-b (3463g).g).TheThe crude crude product product was charged was charged to La reactor to a 100 100 L reactor containing containing ethanol ethanol (28 L), (28 L), and purified and purifiedwater water(7(7L), L),and andthethemixture mixture waswas heated heated to 70to°C 70with °C with stirring, stirring, whereupon whereupon completecomplete

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dissolution was dissolution wasobserved. observed. The The mixture mixture was cooled was cooled to over to 45 °C 45 °C4.5over 4.5andhours hours held and held at that at that 2023 temperatureforforsix temperature sixhours. hours.TheThe mixture mixture was was then then cooledcooled to 20 to 20 °C over°Cfive over five and hours, hours, heldand at held at that temperature that forthree temperature for threehours, hours,and andthethesolids solidsformed formed werewere collected collected by filtration, by filtration, washing washing the the 2023206094 18 Jul contents of contents ofthe the reactor reactor into into the the filter filter with with ethanol (2770mL) ethanol (2770 mL)andand purified purified water water (693 (693 mL). mL). The The purified solid purified solid was wasdried driedininaavacuum vacuumovenoven at °C at 45 45for °C 20 forhours, 20 hours, resulting resulting in purified in purified G-4-b G-4-b

(4116g,g, 75% (4116 75% yield). yield).

Step 8. Step 8. Synthesis Synthesis of of Compound 1 from Compound 1 from G-4-b G-4-b

[0528] IntoInto

[0528] a 20 a 20 L autoclave L autoclave were were charged (15 (15 THFTHF charged L) and L) and G-4-b G-4-b (1503 (1503 g, 1.0 g, 1.0 eq.).10%10% eq.).

palladium palladium onon carbon carbon (76 (76 g, dry g, dry basis) basis) waswas added, added, andautoclave and the the autoclave was three was purged purgedtimes, three times, backfilling with1515p.s.i. backfilling with p.s.i. nitrogen nitrogen each eachtime, time,then thenpurged purged five five times, times, backfilling backfilling with with 19 p.s.i. 19 p.s.i.

hydrogengasgas hydrogen each each time. time. The The mixture mixture was stirred was stirred under under 19 hydrogen 19 p.s.i. p.s.i. hydrogen forhours, for seven sevenand hours, and the autoclave the autoclavewas waspurged purged andand backfilled backfilled withwith nitrogen. nitrogen. The mixture The mixture was filtered was filtered through through diatomaceous diatomaceous earth earth (Celite,1247 (Celite, 1247 g) slurried g) slurried in THF in THF (6L),(6and L),the andautoclave the autoclave was into was rinsed rinsed theinto the filter with filter with an an additional 3.8 LL of additional 3.8 of THF. THF.A second A second batch batch was processed was processed in the in themanner same same using manner using 1538ggofofG-4-b, 1538 G-4-b,andand thethe filtratesfrom filtrates from both both batches batches werewere combined combined and transferred and transferred to a 100toL a 100 L glass reactor. glass reactor. Si-Thiol Si-Thiol(Silicycle, (Silicycle, 757 757g)g)was was added added to the to the reactor, reactor, and and the the temperature temperature was was adjusted toto between adjusted between35-45 35-45 °C and °C and stirred stirred at that at that temperature temperature forhours. for 15 15 hours. The temperature The temperature was was then adjusted then adjustedtoto between between 15-25 15-25 °C the °C and and mixture the mixture was filtered was filtered through through diatomaceous diatomaceous earth earth (Celite, 1091 (Celite, g), slurried 1091 g), slurried in in 88 LL of of THF. THF.TheThe reactor reactor was was washed washed intofilter into the the filter with with additional additional

THF(15(15L).L).TheThe THF combined combined filtrates filtrates were were concentrated concentrated to dryness to dryness underatvacuum under vacuum a at a temperature between temperature 35-40 °C. between 35-40 °C. MTBE MTBE(30(30 L) L) waswas added added to to dissolvethe dissolve theresidue, residue, followed followed by by

purified water(30L), purified water (30 L),andand thethe mixture mixture was was adjusted adjusted to pH to 13pH 132Nwith with 2N aqueous aqueous sodium sodium hydroxide(2.8 hydroxide (2.8L), L),and and stirredfor stirred for1515minutes. minutes. The The layers layers were were separated separated and and the the aqueous aqueous phase phase was adjusted to was adjusted to pH pH 11 with with 2N 2N HCl (3.5 L). HCI (3.5 The The aqueous aqueous mixture mixture was was extracted extracted withwith two two

portions ofdichloromethane portions of dichloromethane(30 (30 L each) L each) and combined and the the combined organic organic extractsextracts werewith were washed washed with purified water(3.8 purified water (3.8 L). L). The The organic organic layer layer waswas concentrated concentrated under under vacuumvacuum at between at between 35-40 °C, 35-40 °C,

providing providing crude crude Compound 1 (3614 Compound 1 (3614 Theg).crude The product crude product was combined was combined with acetonitrile with acetonitrile (18 (18

L) and L) andheated heatedtoto75-85 75-85°C °C with with stirring stirring untilcomplete until complete dissolution dissolution was observed. was observed. Purified Purified water water (18 L) (18 L) was wasadded, added,andand thethe mixture mixture was was againagain heated heated to 75-85 to 75-85 °C. The°C. The temperature temperature was then was then decreasedtoto15-25 decreased 15-25°C °C over over one one hour. hour. The solids The solids formedformed with collected with collected by filtration by filtration and the and the filter cake filter cake washed withacetonitrile washed with acetonitrile(3614 (3614g) g) andand purified purified water water (3614 (3614 g). collected g). The The collected solids solids

weredried were driedininaavacuum vacuumovenoven at°C35for at 35 °C 21 forhours, 21 hours, affording affording Compound Compound 1 of intermediate 1 of intermediate

purity (2220 purity (2220g). g). This Thismaterial material waswas suspended suspended in ethanol in ethanol (15.5 (15.5 L) and water and purified purified (6.7water (6.7 L), and L), and heatedwith heated withstirring stirring to to 76 76°C°Cuntil untilcomplete complete dissolution dissolution waswas observed. observed. The temperature The temperature was was decreasedtoto5050°C°Cover decreased over four four hours, hours, andand heldheld at that at that temperature temperature foradditional for an an additional threethree hours.hours.

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1004799942

Thetemperature The temperaturewaswas decreased decreased to 20to°C20over °C three over three hours,hours, thenatheld then held thatattemperature that temperature for an for an 2023206094 18 Jul 2023

additional six additional six hours. hours. The Thesolids solidsformed formed werewere collected collected by filtration, by filtration, and and the filter the filter cakecake was was washedwith washed with ethanol ethanol (2664 (2664 mL) mL) and purified and purified water water (1.8TheL).solids (1.8 L). The were solids were dried in dried in a vacuum a vacuum ovenatat 45 oven 45°C°Cfor for2626hours, hours,affording affording 1895 1895 g (71% g (71% yield) yield) of pure of pure Compound Compound 1. 1. Example36. Example 36.Synthesis SynthesisofofCompound Compound 1 - Route 1 - Route B B

0 0 o O N O BrN Br N O / NN O0 S S N- S H N N H O H H H G-2-a G-2-a G-9-a G-9-a

0 0 NON N N OH OH N o N a, N 0 O S N O S N O O 0 o I 0'10o -10 o ,- 1 O

G-4-a G-4-a Compound 11 Compound Step 1.1. Synthesis Step Synthesisofoftert-Butyl2-methyl-2-|3-methyl-2-(1,3-oxazol-2-yl)-4,6-dioxo-1-thia- tert-Butyl2-methyl-2-[3-methyl-2-(1,3-oxazol-2-yl)-4,6-dioxo-1-thia 5,7-diaza-5,7-dihydroinden-5-yl]propionate (G-9-a) 5,7-diaza-5,7-dihydroinden-5-yl|propionate (G-9-a)

[0529] IntoInto

[0529] a glassreactor a glass reactorunder undernitrogen nitrogen were were charged charged THF THF(10 (10volumes, volumes,0.01% 0.01% waterbyby water

Karl Fischer), Karl Fischer), and andoxazole oxazole (380.6 (380.6 g, g, 4.04.0 eq.,0.05% eq., 0.05% water water by Karl by Karl Fischer). Fischer). The mixture The mixture was was cooled toto between cooled between-70-70 andand -80 -80 °C, °C, and and n-butyllithium n-butyllithium (2.5 M(2.5 M in hexanes, in hexanes, 2.65 L, 2.65 L, 4.8 4.8 eq.) waseq.) was addedsuch added suchthat thatthe thetemperature temperaturewaswas maintained maintained between between -70 and-70 -80 and °C, -80 °C, mixture and the and thewas mixture was stirred for stirred for an an additional hour atat that additional hour that temperature. Zinc(II) temperature. Zinc (II)chloride chloride(1500 (1500 g, 8.0 g, 8.0 eq.) eq.) waswas added added

in batches, in such that batches, such that the the temperature temperaturewaswas maintained maintained between between -70 and-70 -80and °C.-80 The°C. The was mixture mixture was then warmed then warmed to to between between 15-2515-25 °C,the °C, and andmixture the mixture was stirred was stirred for an additional for an additional two two hours at hours at that temperature. that Pd(PPh3)4(79.5 temperature. Pd(PPh) g, eq.) (79.5 g, 0.05 0.05 and eq.)G-2-a and G-2-a (556.5 (556.5 g, 1.0 g, 1.0 eq.) eq.)added, were were and added, the and the mixturewas mixture washeated heated to to 60 60 °C °C and and stirred stirred for for 27 hours 27 hours at that at that temperature. temperature. Once Once it was it was determinedthat determined thatless lessthan than5.0% 5.0%of of G-2-a G-2-a remained remained by HPLC, by HPLC, the reaction the reaction was was cooled to cooled betweento between 30-40°C°Cand 30-40 andfiltered. filtered. TheThe filtercake filter cakewaswas washed washed with with THFvolumes), THF (two (two volumes), and the and the combined combined filtrates were filtrates combined were combinedand andconcentrated concentratedunder undervacuum. vacuum. Saturated Saturatedaqueous aqueous ammonium chloride ammonium chloride

(10 volumes), (10 volumes),and andmethanol methanol (10 (10 volumes) volumes) were toadded were added to the residue, the residue, and thisand this mixture mixture was was stirred for stirred for one one hour, then filtered. hour, then filtered. The Thefilter filter cake wasslurried cake was slurriedwith withmethanol methanol (5 volumes), (5 volumes), and and purified water purified water(1(1 volume), volume),andand stirredforfor stirred 2 2 hours. hours. TheThe solids solids werewere collected collected by filtration, by filtration, and and dried in dried in aa vacuum oven vacuum oven at 35-45 at 35-45 °Cconstant °C to to constant weight. weight. The solids The dried dried solids were slurried were slurried in 1N in IN

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HCl(15-20 HCI (15-20volumes) volumes) for for 24 hours, 24 hours, and solids and the the solids were were again again collected collected by filtration by filtration and and the the filter filter 2023206094 18 Jul 2023

cake washed cake washed with with purified purified water water until until the the pHthe pH of of filtrate the filtrate reached reached pHThe7. collected pH 7. The collected solids solids weredried were driedininaa vacuum vacuum oven oven at 35-45 at 35-45 °C to°C to constant constant weight. weight. Thesolids The dried dried were solids were slurried slurried in in acetonitrile (8 acetonitrile (8 volumes) volumes) atat80 80°C°Cforfor3030minutes, minutes, then then the the mixture mixture was cooled was cooled to between to between 20-30 20-30 °C and °C andstirred stirred for for 33 hours. hours. The The resulting resulting solids solids were were collected collected by filtration by filtration and and washed washed with with acetonitrile (2 acetonitrile (2 volumes), thendried volumes), then driedinina avacuum vacuumovenoven at 35-45 at 35-45 °C to°C to constant constant weightweight affording affording

pure G-9-a. pure G-9-a.

Alternative Synthesis Alternative Synthesis 2 2 of of G-9-a G-9-a

[0530] To aToreactor

[0530] a reactor waswas combined combined THF THF (482 (482 mL,v/w mL, 6.9 6.9 G-2-a) v/w G-2-a) and oxazole and oxazole (36.08 (36.08 g, 0.51 g, 0.51

w/wG-2-a, w/w G-2-a, 33 equiv.). equiv.). The The contents contentswere were cooled cooledtotoabout -20-20 about °C°Candand2M2Misopropylmagnesium isopropylmagnesium

chloride in chloride in THF THF(304.8 (304.8 g, g, 4.44.4 w/ww/w G-2-a, G-2-a, 3.6 equiv.) 3.6 equiv.) was charged was charged dropwise dropwise maintaining maintaining the the reaction contents reaction contentsatatnot not more morethan than about about -10-10 °C. °C. OnceOnce the addition the addition was complete was complete the reactor the reactor was was cooled once cooled oncemore more to to about about -- °C --15 15 and °C and THF g, THF (35.1 (35.1 0.5 g, w/w0.5 w/w was G-2-a) G-2-a) used was usedthe to rinse to rinse the Grignardsolution Grignard solutionforward. forward. The The solution solution was cooled was cooled to about to about -20 °C -20 and °C zincand zinc chloride chloride (141.8 g,(141.8 g, 2 w/w 2 w/wG-2-a, G-2-a,6 equiv.) 6 equiv.) waswas charged charged portionwise portionwise while while maintaining maintaining the reaction the reaction contents contents at not at not morethan more thanabout about-10-10°C.°C. Once Once the addition the addition was complete was complete the reaction the reaction contents contents weretowarmed were warmed to about 22 about 22 °C over over about about one one hour. hour.To Tothe thereaction waswascharged reaction G-2-a charged G-2-a(70.0 g) and (70.0 and THF THF(35.4 (35.4 g, g, 0.5 w/w 0.5 G-2-a) w/w G-2-a) waswas usedused to rinse to rinse the the material material into into the the reactor. reactor. The The contents contents of theofreactor the reactor were were adjusted to adjusted to about about6060°C°Candand a slurryof of a slurry palladium palladium tetrakistriphenyphosphine tetrakistriphenyphosphine (10.05(10.05 g, 0.14g,w/w 0.14 w/w G-2-a, 0.05 G-2-a, 0.05equiv.) equiv.)ininTHF THF (142 (142 mL, mL, 2 v/w2 G-2-a) v/w G-2-a) was charged. was charged. The The slurry slurry was was rinsed rinsed forward forward with THF with THF (39.4 (39.4 mL,mL, 0.5 0.5 v/w v/w G-2-a) G-2-a) andcontents and the the contents increased increased to aboutto65about 65about °C for °C for about 6 hours. 6 hours. Thecontents The contentsofofthe thereactor reactorwere were adjusted adjusted to about to about 20 and 20 °C °C aand a solution solution of acetic of acetic acid acid (38.8 (38.8 g, g, 0.55 w/w 0.55 w/wG-2-a, G-2-a, 3.73.7 equiv.) equiv.) in in 2-methyltetrahydrofuran 2-methyltetrahydrofuran (662 (662 mL, 9.5mL, v/w 9.5 v/wwas G-2-a) G-2-a) was charged charged over not over not less less than than about aboutthree threehours. hours.The The reaction reaction contents contents werewere then then concentrated concentrated under under vacuum vacuum to about to about 14V 14Vbefore beforebeing being filtered.TheThe filtered. reactor reactor waswas charged charged with with water water (525 (525 mL, 7.5mL, 7.5 v/w v/w G-2-a) G-2-a) whichwas which was then then transferred transferred to to thethe filterand filter andused used to to slurry slurry thethe filtercake. filter cake.The The slurrywaswas slurry filtered filtered

and the and the resulting resulting cake cakewas waswashed washed successively successively with water with water to remove to remove salts. salts. The Thewere solids solids were then removed then removed from from the the filter filter andand combined combined with acetonitrile with acetonitrile (1046 (1046 mL, 15 mL, 15 v/winG-2-a) v/w G-2-a) a in a reactor. The reactor. reactor contents The reactor contentswere were heated heated to reflux to reflux forfor about about 2 hours 2 hours thenthen cooled cooled to about to about 0 °C 0 °C over about over aboutfour fourhours hoursandand held held at at about about 0 °C. 0 °C. The The slurry slurry was filtered. was filtered. The filter The filter cake cake was was washedwith washed with two two portions portions of acetonitrile of acetonitrile (2143 (2 x x 143 mL, mL, 2 v/w2 G-2-a) v/w G-2-a) anddried and then thentodried to G- afford afford G 9-a. 1H NMR 9-a. ¹H NMR(400(400 MHz,MHz, CDCl):CDCl3): 6 12.31 12.31 (s, (s, 1H), 1H), 8.20 8.207.36 (s, 1H), (s, 1H), 7.362.73 (s, 1H), (s, 1H), 2.731.64 (s, 3H), (s, 3H), 1.64 (s, 6H), (s, 1.37 (s, 6H), 1.37 (s, 9H). 9H).

In some

[0531] In some

[0531] embodiments, embodiments, the process the process above can can above be carried outout be carried wherein thethe wherein palladium palladium

catalyst can catalyst be added can be addedasasa adry drysolid soliddirectly directlytotothe thereaction reactionmixture. mixture.

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Alternative Synthesis Alternative Synthesis 3 3 of of G-9-a G-9-a 2023206094 18 Jul 2023

[0532] To aToreactor

[0532] a reactor waswas combined combined (395 (395 THF THF mL,v/w mL, 7.9 7.9 G-2-a) v/w G-2-a) (25.6(25.6 and oxazole and oxazole g, 0.51 g, 0.51

w/wG-2-a, w/w G-2-a, 33 equiv.). equiv.). The The contents contentswere were cooled cooledtotoabout -20-20 about °C°Candand2M2Misopropylmagnesium isopropylmagnesium

chloride in chloride in THF THF(191.4 (191.4 g, g, 3.93.9 w/ww/w G-2-a, G-2-a, 3.2 equiv.) 3.2 equiv.) was charged was charged dropwise dropwise maintaining maintaining the the reaction contents reaction contentsatatnot not more morethan than about about -10-10 °C. °C. OnceOnce the addition the addition was complete was complete the reactor the reactor was was cooled once cooled oncemore more to to about about -15 -15 °C aand °C and a pre-made pre-made solution solution of zincof zinc chloride chloride (102.0 (102.0 g, 2 w/wg,G-2- 2w/w G-2 a, 66 equiv.) a, equiv.) in in 2-methyltetrahydrofuran (349 2-methyltetrahydrofuran (349 mL, mL, 7 v/w) 7 v/w) was charged was charged maintaining maintaining the reaction the reaction

contents at contents at not not more morethan thanabout about -10-10 °C.°C. Once Once the addition the addition was complete, was complete, THFg,(22.07 THF (22.07 0.45 g, 0.45 w/wG-2-a) w/w G-2-a)waswas charged charged andreaction and the the reaction contents contents were warmed were warmed to °C to about 22 about over22 °C over about one about one hour. To hour. Tothe thereaction reactionwas wascharged charged G-2-a G-2-a (50.05 (50.05 g)THF g) and and(22.1 THFg,(22.1 0.45 g, w/w0.45 w/wwasG-2-a) G-2-a) used was used to rinse to rinse the the material into the material into the reactor. reactor. The contentsofofthe The contents thereactor reactorwere wereadjusted adjusted to to about about 45 45 °C °C and palladium and palladiumtetrakistriphenyphosphine tetrakistriphenyphosphine (10.05 (10.05 g, 0.14 g, 0.14 w/w G-2-a, w/w G-2-a, 0.05 equiv.) 0.05 equiv.) was was charged. charged. Thereactor The reactorcontents contentswere were heated heated to about to about 65for 65 °C °C about for about 6 hours. 6 hours. The contents The contents of the reactor of the reactor

wereadjusted were adjustedtotoabout about2020 °C °C and and the the reaction reaction mixture mixture was filtered, was filtered, rinsing rinsing forward forward twice twice with with THF(2(2X x113113 THF mL,mL, 2.262.26 v/w v/w G-2-a). G-2-a). To the To the filtrate filtrate in a reactor in a reactor was charged was charged acetic(27.6 acetic acid acidg,(27.6 g, 0.55 w/w 0.55 w/wG-2-a, G-2-a, 3.73.7 equiv) equiv) overover not not lessless thanthan about about threethree hours. hours. The contents The contents wereabout were aged aged8 about 8 hours atat 22 hours 22 °C°Cbefore beforeconcentrating concentrating to about to about 6 volumes. 6 volumes. The reactor The reactor was charged was charged with methanol with methanol

(249 mL, (249 mL,5 5v/wv/w G-2-a) G-2-a) overover not less not less thanthan about about threethree hours. hours. The reactor The reactor contents contents were were then then aged aged for about for 12hours about 12 hoursatat2020°C°Cbefore before cooling cooling to about to about -15 -15 °C over °C over aboutabout six hours six hours andatheld and held at about about -15 °C. -15 °C. The Theslurry slurrywas was filtered.The filtered. The filtercake filter cakewaswas washed washed with with two portions two portions of methanol of methanol (2 X (2 x 101 mL, 101 mL,2 2v/w v/w G-2-a), G-2-a), one one portion portion of acetonitrile of acetonitrile (100(100 mL, 2mL, v/w 2G-2-a), v/w G-2-a), and and then thentodried dried to afford G-9-a. afford G-9-a.¹H'HNMR NMR (400 (400 MHz, MHz, CDCl): CDC3): 12.31 (s,61H), 12.318.20 (s, (s, 1H),1H), 8.20 (s, (s, 7.36 1H),1H), 2.73 7.36 (s, (s, 1H), 2.73 (s, 3H), 1.64 3H), 1.64(s, (s, 6H), 6H), 1.37 1.37(s, (s, 9H). 9H). Alternative Synthesis 44 of Alternative Synthesis of G-9-a G-9-a

a reactor

[0533] To aToreactor

[0533] waswas THFTHF charged charged (80.5 mL, mL, (80.5 8 v/w 8 v/w G-2-a), G-2-a), oxazole oxazole (5.18 (5.18 g, g, 0.51w/w 0.51 G- G w/w 2-a, 33 equiv.) 2-a, equiv.) and andlithium lithiumchloride chloride(3.80 (3.80g,g,0.38 0.38w/ww/w G-2-a, G-2-a, 3.6 equiv). 3.6 equiv). The contents The contents were were cooled to cooled to about about -20 -20°C °Cand and2M 2M isopropylmagnesium chloride in isopropylmagnesium chloride in THF (43.1 g, THF (43.1 g, 4.31 4.31 w/w w/w G-2-a, G-2-a,

3.6 equiv.) 3.6 equiv.) was wascharged charged dropwise dropwise maintaining maintaining the reaction the reaction contents contents at not at notthan more more than-10 about about -10 °C. Once °C. Oncethe theaddition additionwaswas complete, complete, the reactor the reactor was was cooled cooled oncetomore once more aboutto-20 about -201.9 °C and °C and 1.9 mol/Lzinc mol/L zincchloride chloride(78(78mL,mL, 7.8 7.8 w/w w/w G-2-a, G-2-a, 6 equiv.) 6 equiv.) was charged was charged maintaining maintaining the the reaction reaction contents at contents at not not more morethan thanabout about -10-10 °C.°C. Once Once the addition the addition was complete, was complete, the reaction the reaction contentscontents

werewarmed were warmed to about to about 22over 22 °C °C over aboutabout 30 minutes 30 minutes and and aged foraged aboutfor 45 about 45 To minutes. minutes. the To the reaction was reaction wascharged charged G-2-a G-2-a (9.94 (9.94 g) and g) and the contents the contents ofreactor of the the reactor were adjusted were adjusted to 45 to about about 45 °C. Tetrakis(triphenylphosphine)palladium(0) °C. Tetrakis(triphenylphosphine)palladium(0) (1.39 (1.39 g, 0.14g,w/w 0.14 w/w0.05 G-2-a, G-2-a, 0.05and equiv.) equiv.) THF and THF (9.67 mL, (9.67 mL,1 1v/w v/w G-2-a) G-2-a) werewere thenthen charged. charged. The contents The contents were adjusted were adjusted to about to 65 about °C for65 °C for about about

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12 hours. 12 hours. The Thecontents contentsof of thereactor the reactorwere were adjusted adjusted to about to about 20and 20 °C °Caand a solution solution of acetic of acetic acid acid 2023206094 18 Jul 2023

(5.52 g, (5.52 g, 0.55 0.55 w/w w/wG-2-a, G-2-a, 3.73.7 equiv.) equiv.) in in 2-methyltetrahydrofuran 2-methyltetrahydrofuran (17.5 (17.5 mL, mL, 1.7 v/w 1.7 v/wwas G-2-a) G-2-a) was chargedover charged overnot notless lessthan thanabout about three three hours hours and and aged. aged. The reaction The reaction contents contents were were then then concentratedunder concentrated under vacuum vacuum to about to about 14V.slurry 14V. The The was slurry wastowarmed warmed about 45to°Cabout 45 °C1 for about for about 1 hour, cooled hour, cooledtotoabout about2020°C°C over over about about 2 hours, 2 hours, aged aged at about at about 20 °C20 and°C and cooled cooled to aboutto0about °C 0 °C over about over about44hours hoursandand aged. aged. The The slurry slurry was filtered was filtered at about at about 0 °C 0 °Cthe and andfilter the filter cake cake returned returned to to the reactor. the Water(149.92 reactor. Water (149.92 mL,mL, 15 G-2-a) 15 v/w v/w G-2-a) wascharged was then then charged and thewasslurry and the slurry was for agitated agitated for about 11hour about houratatabout about2020°C°C before before filtration.TheThe filtration. filter filter cake cake waswas washed washed twice twice with with water water before drying before dryingatatabout about4040°C°C under under vacuum. vacuum. The The dry dry were solids solidscharged were charged to a with to a reactor reactor with acetonitrile (149 acetonitrile mL,1515v/wv/w (149 mL, G-2-a) G-2-a) and and heated heated to reflux to reflux (about (about 77 to 77 80 to °C)80 °C)about for for 2about 2 hours, hours, then cooled then cooledtoto0 0°C°Cover overabout about 4 hours 4 hours and and agedaged aboutabout 1 before 1 hour hour before filtration. filtration. The filter The filter cake cake waswashed was washed twice twice with with acetonitrile acetonitrile before before drying drying at about at about 40 °C 40 °C vacuum under under to vacuum to yield yield G-9-a. G-9-a. 'H NMR ¹H NMR (400(400 MHz,MHz, DMSO-d): DMSO-d): 12.31 (s, 6 12.318.20(s,(s, 1H), 1H),1H), 8.20 (s,(s, 7.36 1H), 7.36 1H), (s,(s, 2.73 3H), 1H), 1.64 2.73 (s,(s, 3H), 1.64 (s, 6H), 1.37 6H), 1.37 (s, (s, 9H). 9H). Alternative Synthesis Alternative Synthesis 5 5 of of G-9-a G-9-a

[0534] Oxazole

[0534] Oxazole (1.76 (1.76 g, 0.51 g, 0.51 w/ww/w G-2-a, G-2-a, 2 equiv.)andand 2 equiv.) THF THF (12.5 (12.5 mL,mL, 2.52.5 v/wv/w G-2-a) G-2-a) were were

chargedtotoaareactor charged reactorand andthe thecontents contentscooled cooled to to about about 0 °C. 0 °C. TMPZnCl-LiCl TMPZnCl.LiCl (33v/w (33 mL, 6.6 mL,G- 6.6 v/w G 2-a, 2.4 2-a, equiv.) was 2.4 equiv.) wascharged chargedsuch such that that thethe internal internal temperature temperature was was aboutabout <5 °C.< In 5 °C. In a separate a separate

reactor, G-2-a reactor, (5.03g)g)and G-2-a (5.03 andTHFTHF (40.0 (40.0 mL, mL, 8 v/w8G-2-a) v/w G-2-a) were charged were charged to a and to a reactor reactor and cooled to cooled to about 00 °C. about °C. TMPZnCl.LiCl TMPZnCl-LiCl (16 mL,(16 3.2mL, v/w 3.2 v/w1.2 G-2-a, G-2-a, 1.2was equiv.) equiv.) was charged charged such such that the that the internal temperature internal wasabout temperature was about < 5<°C. 5 °C. The The solutions solutions wereataged were aged at 0about about 0 about °C for °C for1 about hour 1 hour before warming before warmingto to about about 20 and 20 °C °C aging and aging at temperature. at that that temperature. The solution The solution of G-2-aof G-2-a was was transferred to transferred to the the oxazole oxazolesolution. solution.ZnCl ZnCl2 (6.80 (6.80 g, 1.36 g, 1.36 w/w G-2-a, w/w G-2-a, 4 equiv.) 4 equiv.) was charged was charged to the to the reaction mixture reaction mixtureand andthethecontents contents adjusted adjusted to reflux to reflux (about (about 6570to °C). 65 to 70 °C). t-BuXPhos t-BuXPhos Pd G3 Pd G3 precatalyst (0.40 precatalyst (0.40 g,g, 0.08 0.08 w/w w/wG-2-a, G-2-a, 0.04 0.04 equiv.) equiv.) was was then then addedadded as a slurry as a slurry in THFin(10.0 THFmL, (10.0 2 mL, 2 mL/g).TheThe mL/g). reaction reaction mixture mixture was stirred was stirred at reflux at reflux for about for about 60 minutes. 60 minutes. The reaction The reaction mixture mixture wascooled was cooledtotoabout about 20 20 °C °C and and distilled distilled to about to about 10V 1OV pot volume pot volume under vacuum. under vacuum. The The concentratedreaction concentrated reactionmixture mixture waswas slowly slowly quenched quenched into aninto an aqueous aqueous HCl (125 HCI solution solution (125 mL, 1N mL, IN HCl, 2525v/w HCl, v/wG-2-a) G-2-a) andand agitated agitated for for about about 17 hours. 17 hours. The slurry The slurry was filtered was filtered and theand cakethe cake neutralized by neutralized bywashing washing three three times times withwith water water (about (about 50 mL50 mLwash, each each5 wash, 5 v/wThe v/w G-2-a). G-2-a). filter The filter cake was cake wasdried driedatatabout about4040 °C °C under under vacuum. vacuum. The The dry dry were solids solids were charged charged to awith to a reactor reactor with acetonitrile (75.0 acetonitrile mL,1515v/w (75.0 mL, v/w G-2-a) G-2-a) and and heated heated to reflux to reflux (about (about 77 to 77 80 to °C)80for °C)about for about 90 90 minutes,then minutes, thencooled cooledtotoabout about 20 20 °C °C overover about about 4 hours 4 hours and about and aged aged 17 about hours17before hours before filtration. The filtration. filter cake The filter cake was washed was washed twice twice with with acetonitrile acetonitrile (about (about 10each 10 mL mL wash, each wash, 2 2 v/w G- v/w G 2-a) before 2-a) before drying drying atatabout 4040°C°Cunder about vacuum under vacuumtotoyield G-9-a. yield G-9-a.'H¹HNMR (400 MHz, NMR (400 MHz,DMSO- DMSO

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d6): d6): 12.31(s, 612.31 (s, 1H), 1H),8.20 (s, 1H), 8.20(s, 1H),7.36 7.36(s,(s,1H), 1H),2.73 2.73(s,(s,3H), 3H),1.64 1.64(s,(s,6H), 6H),1.37 1.37(s,(s,9H). 9H). 2023206094 18 Jul 2023

AlternativeSynthesis Alternative Synthesis 6 G-9-a 6 of of G-9-a

[0535] Oxazole

[0535] Oxazole (3.38 (3.38 g, 0.51 g, 0.51 w/ww/w G-2-a, G-2-a, 3 equiv.)waswas 3 equiv.) charged charged to toa areactor reactor containing containing THF THF (40.0 mL, (40.0 6 v/w mL, 6 v/w G-2-a) G-2-a) and and the the contents contentswere werecooled cooledtotoabout about-15°C. °C.A A freshlyprepared freshly prepared solution of solution ofTMPMgCl-LiCl (68mL, TMPMgCl-LiCl (68 mL,10.5 10.5w/w w/w G-2-a, G-2-a, 0.85mol/L, 0.85 mol/L,3.63.6equiv.) equiv.) was wascharged chargedsuch such that the that the internal internal temperature wasless temperature was lessthan thanabout about -10 -10 °C. °C. The The temperature temperature was adjusted was adjusted to aboutto about -20 °C, -20 °C, and anda afreshly freshlyprepared preparedsolution solution of of ZnCl2 ZnCl in 2-methyltetrahydrofuran in 2-methyltetrahydrofuran (51 mL, (51 7.8 mL, 7.8 v/w G- v/w G 2-a, 1.9 2-a, 1.9 mol/L, 6.0equiv.) mol/L, 6.0 equiv.)was wascharged charged suchsuch thatthat the the internal internal temperature temperature wasthan was less less about than about -10 °C. -10 °C. The reaction mixture The reaction mixture was was warmed to about warmed to about 20 20 °C over about °C over about 30 30 minutes minutes and and aged. aged. G-2 G-2-

a (6.47 a g) was (6.47 g) wascharged chargedandand thethe reaction reaction mixture mixture warmed warmed to 45 to about about °C. 45 °C. Tetrakis(triphenylphosphine)-palladium Tetrakis(triphenylphosphine)-palladium (0) (0.92 (0) (0.92 g, 0.14 g, 0.14 w/w G-2-a, w/w G-2-a, 0.05 was 0.05 equiv) equiv) then was then chargedand charged andrinsed rinsedforward forward with with THF THF (6.31 mL, (6.3 mL, 1 v/w G-2-a). v/w G-2-a). The temperature The temperature was was adjusted to adjusted to about 6565°C°Cand about andstirred stirredforforabout about 20 20 hours. hours. The The temperature temperature wasadjusted was then then adjusted to aboutto20about °C 20 °C and aa freshly and freshly prepared preparedsolution solutionof of aceticacid acetic acid(3.56 (3.56 g, g, 0.55w/ww/w 0.55 G-2-a, G-2-a, 3.7 equiv.) 3.7 equiv.) in 2-in 2 methyltetrahydrofuran methyltetrahydrofuran (11.0 (11.0 mL, mL, 1.7 G-2-a) 1.7 v/w v/w G-2-a) wasover was added added over about about The 3 hours. 3 hours. slurry The was slurry was aged ananadditional aged additionalabout about 4 hours 4 hours before before distilling distilling to to about about 14V 14V pot volume pot volume under vacuum. under vacuum. The The slurry was slurry waswarmed warmed to about to about 45for 45 °C °C about for about 1 hour, 1 hour, cooledcooled to about to about 20 °C 20 °C over over2 about about hours, 2 hours, aged atat about aged about2020°C°Cforforabout about 6 hours 6 hours and and cooled cooled to about to about 0 °C 0 °C about over over about 4 hours4 and hours and aged foraged for about 88 hours. about hours.TheThe slurry slurry waswas filtered filtered at at about about 0 and 0 °C °C and the filter the filter cake cake returned returned to the to the reactor. reactor.

Water(97.52 Water (97.52g,g,1515v/wv/w G-2-a) G-2-a) was was then then charged charged and theand the slurry slurry was agitated was agitated for4 about for about hours 4 at hours at about 2020°C°Cbefore about beforefiltration. filtration. The The filtercake filter cakewaswas washed washed twicetwice with with water water (about (about 13 mL 13 mL each each wash, 22 v/w wash, v/w G-2-a) before drying G-2-a) before drying to toyield yieldG-9-a. G-9-a.'H¹H NMR (400 MHz, NMR (400 DMSO-d6): MHz, DMSO-d): 6 12.31 12.31 (s, (s, 1H), 8.20 1H), 8.20 (s, (s, 1H), 1H), 7.36 7.36 (s, (s, 1H), 2.73(s, 1H), 2.73 (s, 3H), 3H), 1.64 1.64(s, (s, 6H), 6H),1.37 1.37(s, (s, 9H). 9H). Step 2. Step 2. Synthesis Synthesis of of tert-Butyl2-{7-[(R)-2-(o-methoxyphenyl)-2-(tetrahydro-2H-pyran-4 tert-Butyl 2-{7-[(R)-2-(o-methoxyphenyl)-2-(tetrahydro-2-pyran-4-

yloxy)ethyl]-3-methyl-2-(1,3-oxazol-2-yl)-4,6-dioxo-1-thia-5,7-diaza-5,7-dihydroinden-5 yloxy)ethyl]-3-methyl-2-(1,3-oxazol-2-yl)-4,6-dioxo-1-thia-5,7-diaza-5,7-dihydroinden-5.

yl}-2-methylpropionate (G-4-a) yl}-2-methylpropionate (G-4-a)

[0536] IntoInto

[0536] a glassreactor a glass reactorunder undernitrogen nitrogen were were charged charged G-9-a G-9-a(150.0 (150.0 g, g, 1.0 1.0 eq.) eq.)and andNMP (3 NMP (3

volumes),followed volumes), followed by by G-1-a G-1-a (1.10(1.10 eq.) eq.) and potassium and potassium carbonate carbonate (1.05The (1.05 eq.). eq.). Thewas mixture mixture was heated to heated to 130 130°C°Candand stirredatatthat stirred thattemperature temperatureforfor 16 16 hours. hours. OnceOnce it wasit determined was determined that that less less than 4.6% than of G-9-a 4.6% of remained by G-9-a remained by HPLC, HPLC,the thereaction reaction was was cooled cooled to to between between 25-35 °C, °C, and purified water purified waterwas wasadded added (20(20 volumes) volumes) and stirred and stirred for 2for 2 hours. hours. The solids The solids formed formed were were collected by collected byfiltration, filtration, and the filter and the filter cake cake was washedwith was washed with purified purified water water (5 volumes), (5 volumes), then then dried under dried undervacuum vacuum at room at room temperature. temperature. Theproduct The crude crude product was in was slurried slurried in methanol methanol (8 (8 volumes)andand volumes) thethe mixture mixture was was heated heated to reflux, to reflux, then then cooled cooled to between to between 15-25 15-25 °C. The °C. The solids solids

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formedwere formed were collected collected by by filtration,affording filtration, affording purified purified G-4-a G-4-a (170.7 (170.7 g, 71.2% g, 71.2% yield)yield) as an as an off- off 2023206094 18 Jul 2023

white solid. white solid. Alternative Synthesis Alternative Synthesis of of G-4-a G-4-a

The stock

[0537] The stock

[0537] solution solution of (R)-G-6-a of (R)-G-6-a stock solution stock solution (as prepared according according (as prepared to Alternative to Alternative

Synthesisofof(R)-G-1-a Synthesis (R)-G-1-a discussed discussed above) above) (89.34(89.34 g solution, g solution, 21.67%21.67% (R)-G-1-a (R)-G-1-a wt%, 1.2 wt%, 1.2 equiv.) equiv.) wascharged was chargedto toa areactor reactorcontaining containing G-9-a G-9-a (20.00 (20.00 g, equiv.), g, 1.0 1.0 equiv.), followed followed by rinse by a NMP a NMP rinse forward(3.0 forward (3.0g,g, 0.15 0.15v/w v/wG-9-a) G-9-a) and and addition addition of potassium of potassium carbonate carbonate (7.4 g,(7.4 0.37g,w/w 0.37 w/w G-9-a, G-9-a, 1.05 equiv.). 1.05 equiv.). The Thecontents contentswere were heated heated to about to about 115and°Cstirred 115 °C and stirred for a for a minimum minimum of about of 22 about 22 hours until hours until the the reaction reaction was wasdeemed deemed complete. complete. The contents The contents were tocooled were cooled about to 30 about 30 °C, and °C, and then slowly then slowlyadded added into into drinking drinking water water (200.0 (200.0 g, 10g, v/w 10 G-9-a). v/w G-9-a). Dichloromethane Dichloromethane (211.6 g, (211.6 8 g, 8 v/wG-9-a) v/w G-9-a)waswas then then added, added, and and the solution the solution was agitated was agitated for about for about 30 minutes 30 minutes at aboutat22about °C. 22 °C. Agitationwas Agitation wasstopped stopped andand the the solution solution was was allowed allowed to settle. to settle. The bottom The bottom organic organic layer waslayer was collected and collected andthe thetop topaqueous aqueous layer layer waswas extracted extracted withwith dichloromethane dichloromethane (211.6 (211.6 g, 8 v/wg,G-9-a) 8 v/w G-9-a) at about at 22 °C°Cfor about 22 forabout about3030minutes. minutes. Agitation Agitation was again was again stopped stopped and theand the solution solution was was allowed allowed to settle. to settle. The top aqueous The top aqueouslayer layerwaswas removed removed andbottom and the the bottom organicorganic layer layer was was combined combined with with anotherorganic another organiclayer. layer.TheThe combined combined organic organic layerslayers were distilled were distilled under vacuum under vacuum to to between between about 3V about and about 3V and about 4V 4V pot pot volume. volume. Methanol Methanol(130.0 (130.0g,g, 88 v/w v/w G-9-a) G-9-a) was wasadded addedand andthe the solution was solution wasdistilled distilled down downto to between between about about 3Vabout 3V and and about 4V pot 4V pot volume. volume. Methanol Methanol (79.6 g, 5 (79.6 g, 5 v/wG-9-a) v/w G-9-a)waswas added added and and the slurry the slurry was heated was heated to reflux to reflux (about(about 63 °C) 63 to 69 to 69 for C) for2about about hours.2 hours. Theslurry The slurry was wasthen thencooled cooled to to about about 0 °C0 and °C and filtered. filtered. The filter The filter cakecake was washed was washed with with methanol(31.60 methanol (31.60 g, g, 2 v/w 2 v/w G-9-a) G-9-a) at about at about 0 °C 0and °C dried and dried to afford to afford G-4-a.G-4-a. ¹H NMR 'H NMR (400 MHz, (400 MHz, CDC3):7.70 CDCl): 67.70 (d,= J= (d, J 0.4 0.4 Hz, Hz, 1H), 1H), 7.58 7.58 (dd, (dd, 1.6JHz, J=Hz, J = 1.6 J=Hz, = 7.6 7.61H), Hz, 7.29 1H),(td, 7.29J (td, = 1.6J= Hz,1.6 J Hz, J 8.0 Hz, == 8.0 Hz, 1H), 1H),7.21 7.21(d,(d,J J= 0.8Hz, = 0.8 Hz,1H), 1H), 7.03 7.03 (t,(t,J J= 7.2Hz,Hz, = 7.2 1H), 1H), 6.86 6.86 (d, (d, J =J= 8.08.0 Hz,Hz, 1H), 1H), 5.395.39

(dd, J= (dd, 4.4 Hz, J = 4.4 Hz, JJ= 8.8 Hz, = 8.8 Hz,1H), 1H),4.18-4.15 4.18-4.15 (m,(m, 1H),1H), 3.993.99 (br,(br, 1H),1H), 3.863.86 (s, 3H), (s, 3H), 3.78-3.73(m, 3.78-3.73(

1H), 3.70-3.65(m, 1H), 3.70-3.65 1H), (m,1H), 3.46-3.40 3.46-3.40 (m, (m, 1H), 3.36-3.30 1H), 3.36-3.30 (m, 2.86 (m, 2H), 2H), (s, 2.863H), (s, 1.80 3H),(s, 1.80 (s, 1.76 3H), 3H), 1.76 (s, 3H), (s, 1.76-1.71 (m, 3H), 1.76-1.71 (m,2H), 2H),1.59-1.51 1.59-1.51(m,(m, 1H), 1H), 1.461.46 (s, 9H) (s, 9H) 1.46-1.37 1.46-1.37 (m, (m, 1H). 1H). Step 3. Step 3. Synthesis Synthesis of of Compound Compound 1 1

[0538] IntoInto

[0538] a glassreactor a glass reactorunder undernitrogen nitrogen were were charged charged 99 MMaq. aq. H2SO4 H2SO4(5 volumes)and (5 volumes) and isopropyl alcohol isopropyl alcohol(5(5volumes), volumes),andand the the mixture mixture was cooled was cooled to between to between 5-10 °C.5-10 °C.(150.0 G-4-a G-4-a(150.0g, g,

1.0 eq.) 1.0 eq.) was addedsuch was added suchthat thatthethetemperature temperature of the of the mixture mixture was maintained was maintained betweenbetween 5-10 °C, 5-10 °C, and the and the reaction reactionwas wasstirred stirredatatthat that temperature temperatureforfor2020 hours. hours. OnceOnce it was it was determined determined that nothat no morethan more than0.3% 0.3% of of starting starting G-4-a G-4-a remained remained by HPLC, by HPLC, the mixture the mixture was was poured poured into into purified purified water (20 water (20volumes) volumes) dropwise dropwise and stirred and stirred for one for one hour.hour. The solids The solids formed formed were collected were collected by by filtration, and filtration, and the the filter filtercake cakewas was washed withpurified washed with purifiedwater water (5 (5 volumes). volumes). The was The cake cake was resuspendedin inpurified resuspended purifiedwater water (10(10 volumes) volumes) andpHthewaspH and the was adjusted adjusted to 8-9 to 8-9 with with sodium aqueous aqueous sodium

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hydroxide(20% hydroxide (20% w/w). w/w). The aqueous The aqueous solution solution was extracted was extracted with with ethyl ethyl(three acetate acetate (three of portions portions of 2023206094 18 Jul 2023

5 volumes), 5 andthetheaqueous volumes), and aqueous layer layer was was acidified acidified to pHto4-5 pHwith 4-5 4with 4 MTheHCl. M HCl. Thesolution aqueous aqueous solution wasextracted was extractedwith withethyl ethylacetate acetate(three (threeportions portions of of 10 10 volumes), volumes), and combined and the the combined organicorganic

extracts were extracts werefiltered, filtered, and and concentrated concentratedunder under vacuum vacuum to dryness. to dryness. The residue The residue was dissolved was dissolved in in ethanol/water(7:3, ethanol/water (7:3,1010volumes) volumes) at between at between 70-8070-80 °C,the °C, and andresulting the resulting solution solution was to was cooled cooled to 50 °C 50 °Cover over4 4hours hoursandand held held at at thattemperature that temperature overnight. overnight. The solution The solution wascooled was then then to cooled 20 to 20 °C over °C over3 3hours, hours,and andheld held at at thattemperature that temperature for for at at leastthree least threehours. hours.The The resulting resulting solids solids werewere

collected by collected by filtration, filtration, and the filter and the filter cake cake was washedwith was washed with ethanol/water ethanol/water (7:3, (7:3, 2 volumes), 2 volumes), then then dried under dried undervacuum vacuum to constant to constant weight, weight, affording affording purified purified Compound Compound 1 (110.0 1 (110.0 g, g, 80.5% 80.5% yield, yield, >99%purity >99% purity by byHPLC, HPLC, NMR). NMR).

Alternative Synthesis of Alternative Synthesis of Compound Compound 1 1

[0539] A sulfuric

[0539] A sulfuric acid solution acid solution was prepared was prepared by addition by addition of concentrated of concentrated sulfuric sulfuric acid acid (47 g, (47 g, 4.7 w/w 4.7 w/wG-4-a) G-4-a)to to water water (12 (12 g, 1.2 g, 1.2 v/wv/w G-4-a) G-4-a) followed followed by a (15 by a water water (15 v/w g, 1.5 g, 1.5 v/w rinse G-4-a) G-4-a) rinse forward. 2-Propanol forward. 2-Propanol (37 (37 g, 4.7 g, 4.7 v/w v/w G-4-a) G-4-a) was slowly was slowly chargedcharged to a reactor to a reactor containing containing sulfuric sulfuric acid solution acid solution at at about about99°C°Cwhile whilemaintaining maintaining the the reaction reaction contents contents at noatmore no more than about than about 40 °C, 40 °C, and the and the solution solutionwas wascooled cooled to to about about 5 °C 5 °C. . G-4-a G-4-a (10 g,(10 1.0g,eq.) 1.0 was eq.) charged was charged to the to the solution, solution,

followedbybya a2-propanol followed 2-propanol rinse rinse forward forward (2 g,(20.25 g, 0.25 v/w v/w G-4-a). G-4-a). The contents The contents weretocooled were cooled to about 77 °C°Cand about andstirred stirredfor fora aminimum minimum of about of about 21 hours. 21 hours. The contents The contents wereadded were slowly slowly intoadded into water, and water, andthe theslurry slurry was wasagitated agitatedforforabout about30 30 minutes. minutes. The slurry The slurry was filtered, was filtered, andfilter and the the filter cake was cake washed and was washed and dried dried under under vacuum vacuumfor for about about 44 hours. hours. The The crude crude wet wet cake cake was charged was charged

backtoto the back the reactor, reactor, followed followedbybyadditions additions of of ethyl ethyl acetate acetate (40(40 g, g, 4.44.4 v/wv/w G-4-a) G-4-a) and water and water (100 (100 g, 10 g, v/wG-4-a). 10 v/w G-4-a).TheThe slurry slurry waswas adjusted adjusted to pHtoat pH at about about 8-9 anwith 8-9 with an about20 about20 wt% wt% sodium sodium hydroxidesolution hydroxide solutionat atabout about 22 22 °C,°C, andand thenthen agitated agitated for for about about 30 minutes 30 minutes at about at about 22 °C. 22 The°C. The solution was solution wasallowed allowedto to settle.TheThe settle. toptop organic organic layer layer was was collected collected andbottom and the the bottom aqueousaqueous

layer was layer waswashed washed with with ethyl ethyl acetate acetate (40 (40 g, 4.4 g, 4.4 v/w v/w G-4-a) G-4-a) at about at about 22 °C 22 for°C for 30 about about 30 minutes. minutes.

Thesolution The solutionwas wasallowed allowed to settle,andand to settle, thethe toptop organic organic layer layer was was removed. removed. 2- 2 Methyltetrahydrofuran Methyltetrahydrofuran (86 (86 g, v/w g, 10 10 v/w G-4-a) G-4-a) wasadded, was then then was added, was adjusted adjusted to pH4-5 to pH at about at about 4-5 with an with anabout about4 4N NHClHCl solution solution at about at about 22 The 22 °C. °C. solution The solution was agitated was agitated for30about for about 30 minutes minutes at about at 22 °C°Cand about 22 andthen thenallowed allowed to settle.TheThe to settle. bottom bottom aqueous aqueous layer layer was was extracted extracted with 2- with 2 methyltetrahydrofuran methyltetrahydrofuran (52(52 g, 6g, v/w 6 v/w G-4-a) G-4-a) at about at about 22 °C 22 for°C for about about 30 minutes. 30 minutes. After theAfter the solution was solution wasallowed allowedto to settle,the settle, thebottom bottom aqueous aqueous layer layer was was removed. removed. The layers The organic organicwere layers were combinedandand combined distilledunder distilled under vacuum vacuum (jacket (jacket at about at about < 45 45 °C) C) to4Vabout to about 4V potEthanol pot volume. volume. Ethanol (55.4 g, (55.4 g, 77 v/w v/wG-4-a) G-4-a)was was added added and and the reaction the reaction as distilled as distilled (repeated (repeated twice). twice). Ethanol Ethanol was was again again added(23.7 added (23.7g,3 g,3v/w v/w G-4-a), G-4-a), followed followed by water by water (30 g,(30 g, 3G-4-a). 3 v/w v/w G-4-a). The reaction The reaction wastoheated was heated to about 7575°C°Cand about and then then cooled cooled overover about about 4 hours 4 hours to about to about 50 °C,50 °C,tothen then to 0about about 0 °C °C over over5 about about 5

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hours. The hours. Thereaction reactionis isthen thenaged aged andand filtered, filtered, andand thethe cake cake is washed is washed with with a precooled a precooled mixturemixture 2023206094 18 Jul 2023

of ethanol of (9.5 g, ethanol (9.5 g, 1.2 1.2 v/w v/wG-4-a) G-4-a)andand water water (6 0.6 (6 g, g, 0.6 v/wv/w G-4-a). G-4-a). The resulting The resulting filterfilter cakecake was was washed with washed with dried dried to to afford affordCompound Compound 1.1.¹H IHNMR NMR (400 (400 MHz, MHz, CDCl3): CDCl): 7.706(s, 7.701H), (s, 1H), 7.57 7.57

(dd, J= (dd, 1.6 Hz, J = 1.6 Hz, JJ= 7.6 Hz, = 7.6 Hz,1H), 1H),7.29 7.29(td, (td,JJ= 1.6Hz, = 1.6 Hz,J J= 8.0Hz,Hz, = 8.0 1H), 1H), 7.23 7.23 (d, (d, J =J= 0.40.4 Hz,Hz, 1H), 1H),

7.02 (t, 7.02 (t, J= J = 7.6 7.6 Hz, Hz, 1H), 6.86 (d, 1H), 6.86 (d, JJ= 8.4 Hz, = 8.4 Hz,1H), 1H),5.39 5.39(dd, (dd,J J= 5.6Hz,Hz, = 5.6 J =J= 8.08.0 Hz,Hz,1H), 1H), 4.17 4.17-

4.14 (m, 4.14 1H), (m,1H), 4.04 4.04(br, 1H), (br,1H), 3.86 3.86(s,(s,3H), 3H),3.78-3.67 3.78-3.67 (m,(m, 2H), 2H), 3.46-3.40 3.46-3.40 1H), (m, 3.37-3.32 (m, 1H), 3.37-3.32 (m, (m, 2H), 2.85 2H), 2.85 (s, (s, 3H), 3H), 1.87 1.87(s, (s, 3H), 3H), 1.83 1.83(s, (s, 3H), 3H),1.75-1.72 1.75-1.72(m,(m, 2H), 2H), 1.59-1.51 1.59-1.51 1H), 1H), (m, (m, 1.48-1.39 1.48-1.39

1H). (m, 1H). (m,

Example37. Example 37.Enzymatic Enzymatic Resolution Resolution Screen Screen

[0540] A variety

[0540] A variety of lipase of lipase enzymes enzymes were assayed their for assayed were for their effectiveness effectiveness in the in the kinetic kinetic resolution of resolution ofracemic racemicalcohols alcoholsof of formula formula rac-G-5, rac-G-5, according according to thetofollowing the following procedure. procedure. Test Test substrate rac-G-5-a substrate rac-G-5-a was was dissolved dissolved in either in either toluene toluene or MTBE or MTBE together together with 1 equivalent with 1 equivalent of acyl of acyl donor(vinyl donor (vinylacetate). acetate). 5-10 5-10milligrams milligrams of the of the lipase lipase to be to be tested tested was was added, added, andmixture and the the mixture was was stirred for stirred for 3-10 3-10 hours whilebeing hours while beingsampled sampled periodically periodically for analysis for analysis by chiral by chiral HPLC.HPLC. Table 10Table 10 belowreports below reportsthe theresults resultsofofthe theenzymatic enzymatic resolution resolution screen. screen. ND means ND means "not determined". "not determined".

Table10. Table 10.Results Results of of enzymatic enzymatic resolution resolution screen screen

%Substrate % Substrate % Product % Product Selectivity (% Selectivity (% AUC, 220nm) AUC, 220 nm) Enzyme Enzyme remaining remaining formed formed 28h) R-acetate R-acetate S-acetate S-acetate R-alcohol R-alcohol S-alcohol S-alcohol (28h) (28h) (acetate; 28h) (acetate;

Lipase OF Lipase OF 59.9 59.9 40.1 40.1 16.55 16.55 21.43 21.43 26.27 26.27 32.75 32.75

Acylase Acylase >95 % < 5% ND ND ND > 95% < 5% ND (Amano) ND ND ND ND Lipase PS30 Lipase PS30 > 95 > 95 % % < 5% < 5% ND ND ND ND ND ND ND ND CAL-B CAL-B 21.4 21.4 78.6 78.6 48.87 48.87 30.25 30.25 0 0 20.26 20.26 Lipase PPL Lipase PPL > 95 > 95 % % < 5% < 5% ND ND ND ND ND ND ND ND CAL-A CAL-A 40.4 40.4 59.6 59.6 37.92 37.92 13.96 13.96 4.13 4.13 28.85 28.85 Lipase Lipase Mucor Mucor 58.9 58.9 41.1 41.1 9.74 9.74 30.51 30.51 40.92 40.92 18.18 18.18 Meihei Meihei

Example38. Example 38.Enzymatic Enzymatic resolution resolution substrate substrate screen. screen.

[0541] The The

[0541] enzymatic enzymatic resolution andand resolution hydrolysis of of hydrolysis Example Example 37 was 37 was also also performed on on performed a a wide rangeofofalcohol wide range alcoholsubstrates substrates of of formula formula rac-G-5 rac-G-5 to demonstrate to demonstrate the of the scope scope the of the

transformation.Table transformation. Table 11 11 below below reports reports the results the results of substrate of the the substrate screen. screen.

Table11. Table 11.Results Resultsofof substratescreen substrate screen

Alcoholstructures Alcohol structures %% e.e. of e.e. of followingacyl following acylgroup group alcohol alcohol hydrolysis hydrolysis

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1004799942

OH OH 95-100 95-100 OH OH 95-100 95-100 0 0 Jul 2023 A AO ON CN O O

F F F F OH 95-100 2023206094 18 OH 95-100 O 95-100 OH O O O OH OH 95-100 95-100

O AoOH 95-100 95-100 OH O O O O OH OH 95-100 Ao95-100 OH FF 95-100_ O OH 95-100 OH1 95C10 O O ok O -'OTBDPS OTBDPS F F o NA s OH 95-100 95-100 0!0J_____ OH O AOH OH 95-100 95-100

O 111 - O 'k OTBDPS OTBDPS O O OH Ao95-100 OH F9-0 F 95-100 OH 95-100 OH O O O OH 95-1000 O O F 95-100 F OH 95-100 OH 95-100 F~~, OH ,O O O OH 95-100

95-100 F OH 0 OH Z 95-100 O F F

o O OH 95-100 F F OH 95-100

0 0 CN 1ON O

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1004799942

OH OH 95-100 95-100 OH OH 95-100 95-100 Jul 2023 .\0

O O

F FF ___F__oF

OH OH 95-100 95-100 OH OH 95-100 95-100

.\\O 2023206094 18

o oo O N -' CN CN :Z F F oo F F ____

OH 95-100 95-100 OH OH 95-100 95-100 OH 10 O O O F F 95-100 O OH 0H 95-100 \O 95-100 0 .\o. OH OH 95-100 o 10 F O O 11\' 0OH 95-100 OH 95-100

10 OH OH 95-100 95-100 A 0 0 O ,O

O S F OH 95-100 F Ao95-100 O F9510OH OH 95-100 o

.oeNK"s O S o F__ F OH 95-100

OH 95-100 \O 10F FOH o 0 95-100 F O OH 95-100 A F 95-100 o F OH OH NooA -XN 'z 95-100 ,O 1! F _ 10o F CN ____OH o 95-100 o F F 95-100 OH 10

o O

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Example39. Example 39.Studies Studiesofof Compound Compound1 1 2023206094 18 Jul 2023

[0542] FormForm

[0542] I of ICompound of Compound 1 was 1evaluated was evaluated in three in three studies: studies: Study Study A, A, Study Study B, B, and and Study Study

C. C.

[0543] Study Study

[0543] A evaluated A evaluated the and the safety safety and tolerability tolerability of 30, of 30, 80, 200,80, 200, 500, 500, 800, and 800, 1000 and mg 1000 mg in the in fasted state the fasted state and and 200 mgfollowing 200 mg following a high a high fat fat meal meal (fed(fed state) state) to cohorts to cohorts of 8ofhealthy 8 healthy subjects (6 subjects (6 active active and and22placebo placebocontrol control perper group). group).

[0544] Study Study

[0544] B (5) B (five (fivecohorts (5) cohorts of 8 subjects of 8 subjects (6 active (6 active and 2 placebo)) and 2 placebo)) evaluated evaluated 50 mg 50 mg twice daily twice daily (BID) (BID)(100 (100mg mg daily), daily), 100 100 mg once mg once daily daily (QD)mg(100 (QD) (100 mg 100 daily), daily), 100(200 mg BID mg BID (200 mgdaily), mg daily), 200 200 mg QD(200 mg QD (200mgmgdaily), daily), or or 150 150 mg QD(150 mg QD (150mgmg daily), or daily), or matching matching placebo. placebo. Subjects received Subjects receivedmultiple multipleoral oraldoses doses of of Compound Compound 1 or placebo 1 or placebo for 9 consecutive for 9 consecutive days, days, with a with a single oral single oral dose dose ofofCompound Compound1 or 1placebo or placebo onmorning on the the morning of Day of Day 10. Doses10. Doses were were administered administered

approximately30 30 approximately minutes minutes after after meals. meals.

[0545] Study Study

[0545] C evaluated C evaluated the effects the effects on fractional on fractional de novo de novo lipogenesis lipogenesis (DNL) of a(DNL) single of a single oral dose oral of 20, dose of 20, 50, 50, or or 200 200mgmg Compound Compound 1 compared 1 compared to placebo to placebo (3 ofcohorts (3 cohorts of 10 subjects). 10 subjects).

DNLwaswas DNL assessed assessed by measuring by measuring appearance appearance of de of de novo novo synthesis synthesis of palmitate of palmitate in in very-low very-low density lipoproteins density lipoproteins(VLDL) (VLDL) in response in response to oral to oral fructose fructose (30 minute (30 minute intervals intervals over over 10 10 hours) hours)

using [1 3C]acetate and using [¹³C]acetate andmass mass isotopomer isotopomer distribution distribution analysis analysis (MIDA). (MIDA). The two The twoperiods dosing dosing periods wereseparated were separatedbyby a minimum a minimum of 5 for of 5 days dayswashout for washout of the 13[ C]acetate of the [¹³C]acetate andmedication. and study study medication.

Study A Study A

Table

[0546] Table

[0546] 12 summarizes 12 summarizes PK parameters PK parameters (mean) underunder (mean) fasted fasted conditions conditions of Study of Study A. The A. The

reported factors reported factors may mayvary vary up up to to about about 2%. 2%.

[0547] The The

[0547] comparisons comparisons of plasma of plasma Compound Compound 1 AUCt1 and AUCt and following AUCoc AUC following 200 mg 200 mg Compound Compound 1 under 1 under fed versus fed versus fastedfasted conditions conditions resulted resulted in 90% in 90% confidence confidence intervalsintervals with with lower lower boundsoutside bounds outsidethethe80%80% to 125% to 125% reference reference interval, interval, the geometric the geometric mean(GMRs) mean ratios ratios (GMRs) demonstrated that demonstrated that overall overallplasma Compound 1 1exposure plasmaCompound exposure was wasonly approximately9%9%toto14% onlyapproximately 14% lowerunder lower underfed fedcompared compared to fasted to fasted conditions, conditions, whichwhich may may not be not be a clinically a clinically relevant relevant

difference. The difference. The comparison comparison of of plasma plasma Compound Compound 1 1Cmax Cmaxfollowing following 200 200mg mgCompound Compound 1 under 1 under

fed versus fed versus fasted fastedconditions conditionsindicated maximum indicated maximum plasma plasma Compound Compound 1 1exposure exposurewas was approximately 68% approximately 68%lower lowerunder underfed fed compared comparedtotofasted fasted conditions. conditions. The The plasma plasma Compound Compound 1 1

concentrationversus concentration versustime time profilesdemonstrated profiles demonstrated a delay a delay in first in the the first quantifiable quantifiable concentration concentration

and aa prolonged and prolongedabsorption/distribution absorption/distribution phase phase observed observed under under fed compared fed compared to fastedtoconditions. fasted conditions. However,thethe However, mean mean t½, tv, CL/F, CL/F, and Vz/F and Vz/F valuesvalues and median and median tmaxwere tmax values values were comparable comparable

following 200 following 200 mg Compound mg Compound administered administered under under fed fed andand fasted fasted conditions. conditions.

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Table 12. Table 12. Mean (SD)Pharmacokinetic Mean (SD) Pharmacokinetic Parameters Parameters afterafter a Single a Single DoseDose of Oral of Oral Compound Compound 2023206094 18 Jul 2023

11 to to Healthy Healthy Volunteers Volunteers

PK PK 30 mg 30 mg 80 mg 80 mg 200 mg 200 mg 500 mg 500 mg 800 mg 800 mg 1000 mg 1000 mg Parameters Parameters (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) t112 t1/2 4.5 4.5 ± 1.6 1.6 77 ±2.8 ± 2.8 12 12 ± 1.41.4 10.2 10.2 ±±2.1 2.1 8.2 ± 3.3 8.2 3.3 9.5 2.6 9.5 ± 2.6

1.3 (0.23, 2.0) 1.8 (1.5, 2.0) 1.9 (1.0, 4.0) 1.9 (1.0, 3.0) 2.1 (1.0, 3.0) 2.4 (1.0, 4.0) tm.x(hr)a t (hr) 1.3 (0.23,2.0) 1.8 (1.5,2.0) 1.9 (1.0,4.0) 1.9 (1.0,3.0) 2.1 (1.0,3.0) 2.4 (1.0,4.0)

Cmax (ng/mL) Cmax (ng/mL) 80 ± 66 80 66 101 ± 48 101 48 416 ± 22 416 22 1112 ±±1149 1112 1149 2571 ±±1875 2571 1875 8375± 8375 3207 ± 3207

AUCo-12 NC 395 ± 198 395± 198 1005 545 1005 ± 545 1244± 1244 547 ± 547 NCb NCb AUC012 NC NC NC (h*ng/mL) (h*ng/mL)

AUCo-t AUCo-t 176± 176 104 ± 104 363± 215 363 ± 215 1209± 1209 536 ± 536 2931± 2931 2438 ± 2438 6424± 6424 3184 ± 3184 17419 ±±8403 17419 8403 (h*ng/mL) (h*ng/mL)

AUC. AUCoo 179 ± 115 179 115 402 ±±225 402 225 1254± 1254 ± 616 616 2963± 2963 2458 ± 2458 6464± 6464 3186 ± 3186 17509 ±±8413 17509 8413 (h*ng/mL) (h*ng/mL)

%Metabolite/ % Metabolite/ 8.0% 8.0% 6.6% 6.6% 8.4% 8.4% 5.9% 5.9% 9.7% 9.7% 5.6% 5.6% Parent Ratio Parent Ratio

aaean (Min,Max) Mean (Min,Max) bNC - Not NCNot calculated calculated

Study B Study B

Table

[0548] Table

[0548] 13 summarizes 13 summarizes PK parameters PK parameters of Study of Study B after B after 10 days. TheThe 10 days. reported reported factors factors

mayvary may vary up up to to about about 2%. 2%.

[0549] Maximal

[0549] Maximal exposure exposure (Cmax) (Cmax) of Compound of Compound 1 generally 1 generally increased increased from from Day 1Day 1 to 10 to Day Day 10 and overall and overall exposure exposure(AUCt) (AUCt) increased increased approximately approximately 1.5-3.0 1.5-3.0 fold onfold Day on Day 10 compared 10 compared to Day to Day 1. Mean 1. t/was Mean t½ waswithin within a 2-fold a 2-fold range range independent independent of dose of dose or regimen or regimen on eachon eachday, study study and day, and exhibited aa trend exhibited trend for for longer longermean mean half-lifeonon half-life Day Day 10 versus 10 versus Day 1Day 1 except except at the at the highest highest dose dose (200 mg (200 QD). mg QD).

Table 13. Table 13. Pharmacokinetic Parameters Pharmacokinetic Parameters after after Multiple Multiple Dose Dose of of Compound Compound 1 1 50 mg 50 mg BID BID 100 mg 100 mg QD QD 100 mg 100 BID mg BID 150 mg 150 mg QD QD 200 mg 200 mg QD QD PK Parameter (n=6) (n=6) (n=6)(n=6) (n=6) (n=6) (n=6) (n=6) (n=6) (n=6) PK Parameter Day I1 Day Day Day Day I1 Day Day 10 Day 10 Day I1 Day Day 10 Day 10 Day I1 Day Day 10 Day 10 Day I1 Day Day 10 Day 10 10 10 t12 t/ 3.5 ± 3.5 10.3 ± 10.3 4.3 4.3 ± 7.9 ± 7.9 5.6a 5.6 6.8 ± 6.8 3.9 ± 3.9 6.6 ± 5.9 ± 5.9 5.9± 1 5.9 ± 1

1.6 1.6 6.7 6.7 0.7 0.7 4.5 4.5 1.6 1.6 1.1 1.1 2.8 2.8 3.6 3.6

tmax(hr)b c tmax(hr) 2.4 2.4 4.5 4.5 3.3, 3.3, 4.5 4.5 5.2 5.2 5.2 5.2 3.3 3.3 6.5 6.5 4.7 4.7 3.7 3.7 (1.5,3) (1.5,3) (2,8) (2,8) (1,6) (1,6) (2,12) (2,12) (3,8) (3,8) (2,6) (2,6) (1,3) (1,3) (1,12) (1,12) (2,6) (2,6) (1.5,6) (1.5,6)

Cmax 41 41 ±±14 14 49 ± 49 65 ± 65 54 ±±22 54 22 61.6 61.6 ± 121 ± 121 94 ± 94 111± 111 ± 152±± 152 198 ± 198 (ng/mL)d 15 C (ng/mL)

AUCO 12 143± 143 ± 15

NDe NDe 32 32

234± 234 ± 285±± 285 15

345± 345 ± 56

NDe NDe 40 40

489± 489 ± 52

637± 637 ± 68 68

707± 707 ± 87

1224±± 1224 AUC (h*ng/mL) (h*ng/mL) 29 29 86 86 115 115 78 78 218 218 246 246 191 191 362 362

AUCo-t AUC- 143± 143 ± 403± 403 ± 268± 268 ± 400± 400 ± 345± 345 ± 1122 ± 1122 572± 572 ± 933± 933 ± 868± 868 ± 2051± 2051 ±

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(h*ng/mL) (h*ng/mL) 29 29 104 104 96 96 181 181 77 77 362 362 247 247 424 424 220 220 819 819 2023206094 18 Jul 2023

AUC. AUC. 178 +± 178 NDO NDe 278 + 278 ± NDO NDe 671a 671ª NDO NDe 587 +± 587 NDO NDe 979 + 979 ± NDO NDe (h*ng/mL) (h*ng/mL) 41 41 110 110 254 254 286 286

%Metabolite/ % Metabolite/ 6.4% 6.4% 7.2% 7.2% 4.2% 4.2% 7.3% 7.3% 6.3% 6.3% 5.0% 5.0% 8.3% 8.3% 6.2% 6.2% 6.4% 6.4% 5.2% 5.2% Parent Ratio Parent Ratio

a Value available for one subject, therefore no STD a calculated Value available for one subject, therefore no STD calculated bTmax b D10-steady state Tmax D10-steady state °Mean c (Min, Max) Mean (Min, Max) d Cmax d D10steady Cmax D10 - steady state state °ND -- Not eND- Not done done

Study CC Study

In Study

[0550] In Study

[0550] C, mean C, mean Compound Compound 1 plasma 1 plasma PK parameters PK parameters are summarized are summarized as follows: as follows: at at aa dose dose of of 20 20mg, mg, tmax (hr)a= =1.81.8(1,3), tmax(hr) (1,3), Cmax Cmax (ng/mL) (ng/mL) = 15.5 = 15.5 AUCt AUCt ± 11.5,11.5, (hr*mg/mL) (hr*mg/mL) = 40.0 ± = 40.0 16.0, %Metabolite/Parent 16.0, Ratio %Metabolite/Parent Ratio = 4.3%; = 4.3%; at a at a dose dose of 50of 50tmax mg, mg, (hr) tmax =(hr)a 1.30 (0.99,2), 1.30=(0.99,2), Cmax Cmax

(ng/mL) == 36.5 (ng/mL) 36.5 ± 17.0, 17.0, AUC (hr*mg/mL)= =98.8 AUCt (hr*mg/mL) 98.8= 41.3, 41.3, %Metabolite/Parent %Metabolite/Parent Ratio Ratio= 11%;at = 11%; at aa dose of dose of 200 200mg, mg, tmax (hr)a= =2.02.0(1.3), tmax(hr) (1.3),Cmax (ng/mL)= (ng/mL) Cmax 222 = 222 ± 196, (hr*mg/mL) 196, AUCt AUCt (hr*mg/mL)= = 518. ± 518. 295, %Metabolite/Parent 295, %Metabolite/Parent Ratio Ratio = 5.0%. = 5.0%. a indicates a indicates Mean Mean (Min,The (Min, Max). Max). The factors reported reportedmayfactors may vary up vary uptoto about about2%. 2%. Example40. Example 40.Studies Studiesofof Compound Compound1 in1 Subjects in Subjects with with Normal Normal and Impaired and Impaired Hepatic Hepatic

Function Function

[0551] ThisThis

[0551] study study evaluates evaluates Form Form I of I of Compound in subjects 1 in1 subjects Compound with with normal andand normal impaired impaired

hepatic function hepatic functionand andtotoevaluate evaluatethethesafety safetyandand tolerabilityof of tolerability Compound Compound 1 single-dose 1 single-dose

administrationininsubjects administration subjectswith withnormal normal andand impaired impaired hepatic hepatic function. function.

[0552] The The

[0552] as as are are cohorts cohorts Cohort1 1(Mild follows:Cohort follows: (MildHepatic includes Impairment)includes HepaticImpairment) approximately20 20 approximately subjects subjects (10 (10 per per group group (mildly (mildly impaired impaired and matched and matched controls)controls) for 8 evaluable for 8 evaluable

per group); per group); Cohort Cohort2 2(Moderate (Moderate Hepatic Hepatic Impairment) Impairment) includes includes approximately approximately 20(10 20 subjects subjects per (10 per group(moderately group (moderately impaired impaired and and matched matched controls) controls) for 8 evaluable for 8 evaluable per group); per group); and3 and Cohort Cohort 3 (Severe Hepatic (Severe HepaticImpairment) Impairment) includes includes approximately approximately 20 subjects 20 subjects (10 per (10 per(severely group group (severely impairedand impaired andmatched matched controls) controls) for for 8 evaluable 8 evaluable per group) per group)

[0553] Eligible

[0553] Eligible subjects subjects include include male male and and non-pregnant/non-lactating non-pregnant/non-lactating femaleages female subjects, subjects, ages 18-70 years 18-70 yearsinclusive inclusivewith withmildly mildly impaired, impaired, moderately moderately impaired, impaired, severely severely impaired, impaired, and and normal normal hepatic function. hepatic function. Subjects Subjectswill willbebecurrent currentnon-smokers non-smokers (no ofusetobacco, (no use of tobacco, nicotine-containing nicotine-containing

or THC or containing THC containing products products within within the last the last 14 days). 14 days). Each Each subject subject in theincontrol the control group group will bewill be matched for matched for age (± (± 10 10 years), years),gender, race, gender, andand race, body mass body index mass (± (± index 15%15%1818 < BMI BMI <36 36 kg/m2) kg/m2) with aa subject with subject in in the the hepatic hepatic impairment impairment group. group. A subject A subject with with normal normal hepatic hepatic function function may may serve as serve as aa matched matchedcontrol control across across cohorts cohorts but but may may only only serve serve as a matched as a matched control control to one to one hepatic hepatic

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impairedsubject impaired subjectwithin withina cohort. a cohort.Cohorts Cohorts 1 and 1 and 2 may 2 may be dosed be dosed in parallel, in parallel, with dosing with dosing for for 2023206094 18 Jul 2023

Cohort3 3(severe Cohort (severehepatic hepaticimpairment) impairment) proceeding proceeding after after reviewreview of safety of safety and preliminary and preliminary PK data PK data (if available) (if available) from hepatically impaired from hepatically impairedsubjects subjects in in theprevious the previous cohorts. cohorts. Based Based on on the the cumulativereview cumulative review of of safety safety andand PK data PK data from from Cohorts Cohorts 1 and 1 and 2, 2, Cohort Cohort 3 may or3may maynotorbemay not be initiated at initiated atthe thediscretion discretion of of the the investigator investigator and Sponsor.Dosing and Sponsor. Dosingin in subjects subjects with with normal normal hepatic hepatic

function will function will begin beginafter after aa matched matched subject subject with with hepatic hepatic impairment impairment has completed has completed all Day all 1 PKDay 1 PK assessments(e.g., assessments (e.g., 9696hours hourspostdose). postdose).

[0554] Eligible

[0554] Eligible may subjectsmay subjects exhibitvarying exhibit hepatic impairment degreesofofhepatic varyingdegrees and matched impairment and matched healthy controls. healthy controls. Those Thosesubjects subjectswith with hepatic hepatic impairment impairment willcategorized will be be categorized basedtheupon based upon the CPTclassification CPT classificationsystem system forfor hepatic hepatic impairment impairment as recommended as recommended by the by the United United States FDA States FDA and international and international guidance guidancedocuments documents (U.S. (U.S.Department Department of of Health Healthand andHuman Services Food Human Services Food and Drug and Drug Administration Administration Center Center for for Drug Drug Evaluation Evaluation and and Research Research (CDER); Centerfor (CDER); Center for Biologics Evaluation Biologics Evaluation and and Research Research (CBER) 2003). Within (CBER) 2003). Withinthe the Child-Pugh-Turcotte Child-Pugh-Turcotte (CPT) (CPT) system, subjects system, subjectswill willbebeassigned assignedto toClass Class A, A, B, B, or or C (CPT C (CPT ClassClass A, B, A, or B, C) or C) based based on a on a cumulativescore cumulative scoreevaluating evaluating thethe presence presence and and severity severity of hyperbilirubinemia, of hyperbilirubinemia, hypoalbuminemia, hypoalbuminemia,

prolongationofofINR prolongation INR forfor coagulation coagulation time, time, ascites, ascites, and and hepatic hepatic encephalopathy. encephalopathy. Classification Classification of of hepatic impairment hepatic impairment will will be be assigned assigned as follows: as follows: (1) Mild: (1) Mild: ClassClass A,score A, CPT CPTofscore 5-6; of 5-6; (2) (2) Moderate:Class Moderate: Class B, B, CPTCPT score score of 7-9; of 7-9; and Severe: and (3) (3) Severe: Class Class C, CPTC, CPTofscore score of 10-15. 10-15.

[0555] Also,

[0555] Also, subjects subjects with with hepaticimpairment hepatic impairmentandandhealthy healthymatched matchedcontrols controlsmay maybebe enrolled. The enrolled. Thecontrol controlgroup groupmaymay consist consist of matched of matched healthy healthy subjects subjects with normal with normal hepatic hepatic function. function.

Inclusion Criteria Inclusion Criteria

[0556] Additional

[0556] Additional inclusion inclusion criteria may criteria maybebeused, used, for for example: example:

• Aside fromhepatic Aside from hepatic insufficiency, insufficiency, the the subject subject must, must, in opinion in the the opinion ofinvestigator, of the the investigator, be sufficiently healthy be sufficiently healthyforforstudy study participation participation based based upon upon medical medical history,history, physicalphysical

examination,vital examination, vitalsigns, signs,and andscreening screening laboratory laboratory evaluations evaluations

• May havediagnosis May have diagnosisofofchronic chronic(>(>6 months), 6 months), stablehepatic stable hepaticimpairment impairment with with no no

clinically significant clinically significantchanges changeswithin within 33 months (or 90 months (or 90 days) days)prior prior toto study studydrug drug administration(Day administration (Day1) 1) • May meet May meet allall ofof thefollowing the following laboratory laboratory parameters parameters at Screening: at Screening:

• alanine aminotransferase alanine (previously serum aminotransferase (previously serum glutamic glutamic pyruvic pyruvictransaminase transaminase (ALT)value (ALT) value <1010X xupper upperlimit limit of of normal normal (ULN) (ULN)

• aspartate aminotransferase aspartate aminotransferase(AST) (AST) value value< 10 10 xX ULN ULN

• Absolute neutrophil count Absolute neutrophil count > 1,000/mm³ 1,000/mm3 • Platelets 25,000/mm³3 Platelets> 25,000/mm

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• Hemoglobin Hemoglobin >88 g/dL g/dL 2023206094 18 Jul 2023

• a-fetoprotein -fetoprotein <5050ng/mL ng/mL • Subjects with Subjects withmild mildhepatic hepatic impairment impairment must must have ahave scorea on score the on thePugh Child Child Pugh Turcotte Turcotte scale of scale 5-6 at of 5-6 at Screening. Screening.IfIfa asubject's subject'sscore scorechanges changes during during the the course course ofstudy, of the the study, the score at the score at Screening Screeningwill willbebeused usedforforclassification classification • Subjects with Subjects moderate hepatic with moderate hepatic impairment impairmentmust musthave have a score a score on on thethe Child Child Pugh Pugh

Turcotte scaleofof7-9 Turcotte scale 7-9atatScreening. Screening. If If a subject's a subject's score score changes changes duringduring the course the course of of the study, the the study, the score score at at Screening Screeningwill willbebeused used forfor classification classification

• Subjects with Subjects with severe severe hepatic hepatic impairment impairmentmust must have have a score a score on Child on the the Child Pugh Pugh Turcotte scaleofof10-15 Turcotte scale 10-15atatScreening. Screening. If If a subject'sscore a subject's score changes changes during during the course the course of of the study, the the study, the score score at at Screening Screeningwill willbebeused used forfor classification. classification.

• Subjects with Subjects withhepatic hepaticimpairment impairment withwith comorbid comorbid diseases diseases not associated not associated with with hepatic hepatic impairmentrequiring impairment requiring medication(s) medication(s) must must be taking be taking the medication(s) the medication(s) withoutwithout a changeain change in dose for dose for at at least least 44 weeks (or 55half-lives, weeks (or half-lives, whichever whichever is is longer)prior longer) priortotoScreening. Screening. AnyAny

changeininthe change thedosage dosageduring during this this timeframe timeframe should should be reviewed be reviewed and approved and approved by the by the Sponsor. Sponsor.

Dosingand Dosing andAdministration Administration

[0557]

[0557] OnDay On Day1 subjects 1 subjects will will receive receive a single a single oral oral dose dose of mg of 20 20 Compound mg Compound 1 (2 X 101 mg (2 x 10 mg capsule) orally. capsule) orally. Dosing Dosingininsubjects subjectswith with normal normal hepatic hepatic function function will will beginbegin after after a matched a matched

subject with subject with hepatic hepaticimpairment impairmenthas has completed completed all1Day all Day 1 PK assessments PK assessments (e.g., 96(e.g., hours96 hours postdose). Cohorts1 and postdose). Cohorts 1 and 2 may 2 may be dosed be dosed in parallel, in parallel, with with dosing dosing for Cohort for Cohort 3 (severe 3 (severe hepatichepatic

impairment)proceeding impairment) proceeding after after review review of safety of safety and preliminary and preliminary PK PK data (ifdata (if available) available) from from hepatic impaired hepatic impairedsubjects subjectsin inthetheprevious previous cohorts. cohorts. Based Based on cumulative on the the cumulative review review of and of safety safety and PKdata PK datafrom from Cohorts Cohorts 1 and 1 and 2, Cohort 2, Cohort 3 may3 or may may or may not not be initiated be initiated at the discretion at the discretion of the of the investigator and investigator andSponsor. Sponsor.Pharmacokinetic Pharmacokinetic Assessments Assessments andAssessments and other other Assessments (as (as discussed discussed above) may above) may be be performed. performed.

[0558]

[0558] Example 41.Studies Example 41. Compound StudiesCompound withwith in Subjects 1 in1 Subjects NASHNASH

[0559]

[0559] This This study safety,tolerability, evaluatesthethesafety, studyevaluates tolerability, and Form efficacyofofForm andefficacy I of I of Compound 1 in 1 in Compound subjects with subjects withNASH. NASH. Toeligible To be be eligible to participate, to participate, subjects subjects may may have hepatic have hepatic steatosis steatosis and and increased liver increased liver stiffness stiffness as as assessed assessed by byMagnetic Magnetic Resonance Resonance Imaging Imaging - Protein - Protein Density Density Fat Fat Fraction (MRI-PDFF) Fraction andMagnetic (MRI-PDFF) and MagneticResonance Resonance Elastography Elastography (MRE), (MRE), respectively,or ora respectively, a historical liver historical liver biopsy consistent with biopsy consistent withNASH NASH and noncirrhotic and noncirrhotic fibrosis. fibrosis. Any subject Any subject with history with history

of decompensated of liver decompensated liver disease, disease, including including ascites, ascites, hepatic hepatic encephalopathy encephalopathy or variceal or variceal bleeding bleeding

maybebeineligible. may ineligible.

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[0560] Subjects

[0560] Subjects meeting meeting the study's the study's entry criteria will bewill entry criteria be randomly randomly assigned in a 2:2:1 in assigned a 2:2:1 ratio ratio 2023206094 18 Jul 2023

to 11 of to of 33 different different treatment groups,A,A,B,B,and treatment groups, andC as C as discussed discussed below. below. Randomization Randomization may be may be stratified by stratified by the the presence or absence presence or absenceofofdiabetes diabetesmellitus mellitus as as determined determined by medical by medical history, history, use use of medication of forindication medication for indicationofofdiabetes diabetesmellitus, mellitus,or orbased based on on Screening Screening lab values lab values if previously if previously

undiagnosed (i.e., undiagnosed (i.e., hemoglobin hemoglobin Alc Alc > 6.5% 6.5%OROR fastingplasma fasting plasmaglucose glucose >126126 mg/dL). mg/dL). Study Study

drugs will drugs will be beadministered administeredforfor a totalofof1212weeks a total weeks from from the the Baseline/Day Baseline/Day 1 visit. 1 visit.

[0561] 5 milligrams

[0561] 5 milligrams 1 or 1placebo, of Compound of Compound or placebo, or 10 of of 10 milligrams or milligrams Compound 1 or 1 Compound or placebo, may placebo, maybebe administered administered withwith or without or without food daily. food once once daily. Studydosing Study drug drug and dosing and administrationmay administration may occur occur as follows as follows based based on treatment on treatment group group randomization: randomization:

• Treatment Group Treatment GroupA: A: Compound Compound 1 5 administered 15 mg mg administered orally orally once once daily; daily;

• Treatment Group Treatment GroupB:B:Compound Compound 120 1 20 mg mg administered administered orallyonce orally oncedaily; daily; • TreatmentGroup Treatment Group C: Placebo C: Placebo administered administered orally orally once once daily. daily.

[0562] Subjects

[0562] Subjects may bemay be evaluated evaluated during during the theatstudies studies at weeks weeks 0, 0, 4,1, 5, 1, 2, 3, 2, 6, 3, 4, 7, 5, 8, 6, 9,7,10, 8, 9, 10, 11, 12, 11, 12, 13, 13, 14, 14, 15, 15, 16, 16, 17, 17, 18, 18, 19, 19, 20, 20, 21, 21, 22, 22, 23, 23, or or 24 24 weeks weeksbyby thefollowing: the following: • QoLQuestionnaires QoL Questionnaires (Short (Short Form Form(36) (36)Health HealthSurvey Survey (SF-36),World (SF-36), World Productivity Productivity andand

Activity Activity Impairment (WPAI),and Impairment (WPAI), andChronic ChronicLiver LiverDisease Diseasequestionnaire questionnaire (CLDQ)). (CLDQ)).Note: Note: It isisrecommended It that QoL recommended that QoLquestionnaires questionnaires be be completed completedprior prior to to any any study study procedures procedures

being performed being performed andand prior prior to to thethe subject subject seeing seeing a health a health carecare provider. provider.

• Symptomdriven Symptom drivenphysical physicalexamination examination • Recordvital Record vitalsigns, signs, waist waistcircumference, circumference,andand bodybody weight weight

• Obtain blood Obtain blood samples samplesfor forChemistry, Chemistry,Hematology, Hematology, Coagulation Coagulation Panel, Panel, Lipid Lipid Profile, Profile,

HemoglobinAlc, Hemoglobin Alc,Biomarkers, Biomarkers, or Genomic or Genomic testing testing (only(only if subject if the the subject consented consented to to participate in the participate in the optional genomicresearch) optional genomic research) • Conduct standard Conduct standard 12-Lead 12-Lead ECG ECG • PerformFibroScan® Perform FibroScano(if (if available) available)

• Collect urine Collect urine samples samplesforforurine urine pregnancy pregnancy test test for for females females of child of child bearing bearing potential potential only only or biomarkers or biomarkers

• Collect stool Collect stool sample sampleforforBiomarkers Biomarkers (see(see Study Study Reference Reference Binder Binder for instructions) for instructions)

• Dispense study Dispense study drugs, drugs, and and provide provide subject subject with with instruction instruction on appropriate dosing on appropriate dosing and and

administration; subject administration; subjectwill willtake takethe theBaseline/Day Baseline/Day 1 dose 1 dose of study of study drugsdrugs on-site on-site

• Collect MRE Collect data MRE data

• Collect MRI-PDFF Collect data MRI-PDFF data

• Recordall Record all concomitant concomitant medications medications that that the subject the subject has taken has taken since since the previous the previous visit visit • Recordanyany Record serious serious adverse adverse events events andadverse and all all adverse events events occurring occurring since since the the Screening Screening

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visit. visit.

2023206094 18 Jul 2023

[0563] While

[0563] While we have we have described described a number a number of embodiments of embodiments of this of this invention, isis apparent it it invention, apparent that our that our basic examplesmaymay basic examples be altered be altered to provide to provide otherother embodiments embodiments that utilize that utilize the compounds the compounds

and methods and methodsof of thisinvention. this invention. Therefore, Therefore, it will it will be be appreciated appreciated that that the the scope scope of this of this invention invention

is to is tobe be defined by the defined by the appended appended claims claims rather rather than than by the by the specific specific embodiments embodiments thatbeen that have have been representedbybyway represented wayof of example. example.

[0564] By wayByofway

[0564] clarification and forand of clarification avoidance of doubt,of for avoidance asdoubt, as used used herein exceptand andherein except where where the context the context requires requires otherwise, otherwise,the theterm term "comprise" "comprise" and variations and variations ofterm, of the the term, such such as as "comprising","comprises" "comprising", "comprises" and and "comprised", "comprised", areintended are not not intended to exclude to exclude further further additions, additions,

components,integers components, integers or or steps. steps.

[0565] to any to Reference

[0565] Reference anyart prior in art prior the in the specification specification annot is not is an acknowledgement acknowledgement or or suggestionthat suggestion thatthis this prior prior art art forms part ofofthe forms part the common common general general knowledge knowledge in any in any jurisdiction jurisdiction or or that this that this prior prior art artcould could reasonably beexpected reasonably be expectedtotobebecombined combined with with any other any other piece piece of prior of prior art art by a skilled person in the art. by a skilled person in the art.

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Claims (1)

1005912781 CLAIMS CLAIMS We claim: 07 May 2025 2023206094 07 May 2025 We claim:

1. 1. A compound A compound ofofthe theformula: formula:

HO O

,, or or a salt thereof. a salt thereof. 2023206094

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